SMARCA4

  • 2
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
SMARCA4 (HGNC:11100) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
SNF2L4
Alias symbols
hSNF2b, BRG1, BAF190, SNF2, SWI2, SNF2-BETA, SNF2LB, FLJ39786
%HI
2.95(Read more about the DECIPHER Haploinsufficiency Index)
pLI
1(Read more about gnomAD pLI score)
LOEUF
0.06(Read more about gnomAD LOEUF score)
Cytoband
19p13.2
Genomic Coordinates
GRCh37/hg19: chr19:11071706-11172949 NCBI Ensembl UCSC
GRCh38/hg38: chr19:10961030-11062273 NCBI Ensembl UCSC
MANE Select Transcript
NM_003072.5 ENST00000344626.10 (Read more about MANE Select)
MANE Plus Clinical Transcript(s)
NM_001387283.1 ENST00000646693.2 (Read more about MANE Plus Clinical)
Function
Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Component of the CREST-BRG1 complex, a multiprotein complex that regulates promoter activation by orchestrating the calcium- dependent release of a repressor comp... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-17145
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Emerging Evidence for Haploinsufficiency (2)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
07/13/2022

Haploinsufficiency (HI) Score Details

HI Score:
2
HI Evidence Strength:
Emerging Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • rhabdoid tumor predisposition syndrome 2 Monarch
HI Evidence:
  • PUBMED: 20137775
    SMARCA4 has definitive association with rhabdoid tumor predisposition syndrome 2 (OMIM 613325; may act as a tumor suppressor) and Coffin-Siris syndrome 4 (CSS, OMIM: 614609; autosomal dominant). Malignant rhabdoid tumors can occur in almost any anatomic location (GeneReviews: https://www.ncbi.nlm.nih.gov/books/NBK469816/). Schneppenheim et al. (2010): The authors describe a heterozygous nonsense mutation c.3565C>T (p.Arg1189*, in exon 26/34) in SMARCA4 in germline DNA derived from an 18-month-old female with a diagnosis of rhabdoid tumor (RT) of the kidney. This mutation was detected in the homozygous state in her tumor tissue. It was also detected in the homozygous state in the rhabdoid tumor tissue of her deceased full sister, and in the heterozygous state in the germline of her apparently unaffected father but not in her mother. The authors note that both siblings lacked expression of the SMARCA4 protein; and RT-PCR on the patient's lymphoblastoid cells and expression studies indicated nonsense-mediated. Additionally, copy-neutral LOH encompassing the SMARCA4 locus in 19p13 was identified as a “second hit” in the tumor cells on the background of a balanced genome.
  • PUBMED: 23775540
    Witkowski et al. (2013): Describes the case of a woman originally diagnosed with an ovarian immature teratoma following a C-section in 1993. The woman's infant was simultaneously diagnosed with a clonally distinct intracerebral immature teratoma. The authors performed whole exome sequencing on the constitutional DNA from both individuals and discovered a c.3533G>A; p.Trp1178* (in exon 25 of 34) mutation in SMARCA4 in both mother and child; the authors demonstrated that this mutation was subject to nonsense-mediated decay. The authors report that "histopathological and immunohistochemical re-analysis of the daughter's tumour revealed that it was indeed a rhabdoid tumour (atypical teratoid/rhabdoid tumour). In this context, the original pathology report of the mother's ovarian tumour was re-interpreted as describing a malignant rhabdoid tumour of the ovary."
  • PUBMED: 33907931
    PMID 3: Small cell carcinoma of the ovary, hypercalcemic type falls within the category of extracranial rhabdoid tumors. Pastorczak et al (Familial Cancer; PMID: 33907931 ; 2021) report on a family with two children carrying pathogenic germline variants in SMARCA4 with pediatric-age ovarian neoplasms. The two siblings had an exon 24 of 34 nonsense variant in SMARCA4 gene (c.3310C > T) inherited from their father (Fig. 1).
  • PUBMED: 25060813
    In a 2014 study Hasselblatt et al (PMID: 25060813; Acta Neuropathol) describes three separate germline nonsense variants (Table 1; patient 4 – paternally inherited, patient 7 – inheritance unknown, and patient 9 – paternally inherited). All individuals were of pediatric age with : SMARCA4-mutated atypical teratoid/rhabdoid tumors.
  • PUBMED: 32903985
    In a 2020 study by Mitrakos et al (Mol Syndromology; PMID: 32903985 ), chromosomal microarray analysis identified a 428-kb deletion in chromosome 19 which included the SMARCA4 gene (inheritance status unknown and several adjacent genes) . The main phenotypical features were noted to be that of Coffin-Siris syndrome and ranged from developmental delay, intellectual disability (ID), behavioral abnormalities, hypoplastic or absent fifth fingernails, feeding difficulties, as well as coarse facial features. These aberrations were less severe than those in patients with typical Coffin-Siris syndrome.
HI Evidence Comments:
Loss of function mutations in SMARCA4 have been associated with rhabdoid tumor predisposition syndrome. Additional entries: Hasselblatt et al. (2011) (PMID: 21566516) also report a case of a rhabdoid tumor in a 9-month-old boy due to a homozygous SMARCA4 mutation [c.2032C>T (p.Q678*)]." The authors were unable to perform germline testing on the proband. Tsurusaki et al. (2012, PMID 22426308) identified 5 missense mutations and an in-frame deletion in the SMARCA4 gene in individuals with a nonspecific syndromic form of intellectual disability (MRD16; 614609). While germline heterozygous truncating mutation in SMARCA4 has been reported in individuals with rhabdoid tumor predisposition syndrome-2 (613235), all mutations in SMARCA4 [in this study] were nontruncating, implying that they exert gain-of-function or dominant-negative effects." See also PMIDs 23637025, 23929686. Based on above, for rhabdoid tumor predisposition, at least 5 families with over 7 individuals have exhibited early onset familial cancers related to nonsense variants in SMARCA4. Of note, SMARCA4 relative to SMARCB1 represents 5-15% of the cases attributed to rhabdoid tumor predisposition vs. 85-95% for the more classically mutated gene SMARCB1 (GeneReviews). To date, missense variants though have been more readily described vs. loss of function for variants in SMARCA4. For Coffin-Siris syndrome; heterozygous mutations (mostly missense) in SMARCA4 have been reported in at least 15 patients but none loss of function [PMID: 23637025 (6 patients); PMID: 31160358 , (1 case report , possible dominant negative effect; PMID: 31530938 (7 patients)]. However reports on focal copy number variants of 19p13.2 affecting SMARCA4 are rare and typically include additional genes. Overall haploinsufficiency of SMARCA4 could be proposed but produces a milder Coffin-Siris syndrome phenotype.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000019.9) (NC_000019.10)