ANKRD26 |
- 0
Haplo
Score - 0
Triplo
Score
Gene Facts External Data Attribution
- HGNC Symbol
- ANKRD26 (HGNC:29186) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
- HGNC Name
- ankyrin repeat domain containing 26
- Gene type
- protein-coding gene
- Locus type
- gene with protein product
- Previous symbols
- THC2
- Alias symbols
- KIAA1074
- %HI
- 88.32(Read more about the DECIPHER Haploinsufficiency Index)
- pLI
- 0(Read more about gnomAD pLI score)
- LOEUF
- 0.73(Read more about gnomAD LOEUF score)
- Cytoband
- 10p12.1
- Genomic Coordinates
-
GRCh37/hg19: chr10:27293045-27389423 NCBI Ensembl UCSC GRCh38/hg38: chr10:26947582-27100494 NCBI Ensembl UCSC - MANE Select Transcript
- NM_014915.3 ENST00000376087.5 (Read more about MANE Select)
- Function
- Acts as a regulator of adipogenesis. Involved in the regulation of the feeding behavior. {ECO:0000250|UniProtKB:Q811D2}. (Source: Uniprot)
Dosage Sensitivity Summary (Gene)
Dosage ID:
ISCA-11198
ClinGen Curation ID:
CCID:006667
Curation Status:
Complete
Issue Type:
Dosage Curation -
Gene
Haploinsufficiency:
No Evidence for Haploinsufficiency
(0)
Triplosensitivity:
No Evidence for Triplosensitivity
(0)
Assoc. with Reduced Penetrance:
Yes
PMID: 24030261 - Increased risk of developing myeloid malignancy (MDS, AML, CML) however, this outcome was only observed in 12 of 44 families with ANRKD26 mutations, indicating the penetrance for malignancies was not complete, and other genetic and/or environmental factors may have contributed to the development of these disorders.
Last Evaluated:
10/10/2023
Haploinsufficiency (HI) Score Details
HI Score:
0
HI Evidence Strength:
No Evidence for Haploinsufficiency
(Disclaimer)
HI Disease:
- thrombocytopenia 2 Monarch
HI Evidence Comments:
ANKRD26 is associated with an autosomal-dominant form of thrombocytopenia. This disorder is characterized by moderate thrombocytopenia, normal platelet size, and mild to absent bleeding tendency. There is currently no evidence supporting a pathogenic role of haploinsufficiency or triplosensitivity of ANKRD26. Focal deletions or duplications of ANKRD26 are not reported in the literature or databases associated with any malignancy. Haploinsufficiency predictors suggest ANKRD26 is not sensitive to loss of function mutations. ANKRD26 related thrombocytopenia mutations that have been reported are 5'UTR substitutions and N-terminal truncating mutations of ANKRD26, which increase MAPK/ERK signaling (PMID: 28100250). Individuals with ANKRD26 related thrombocytopenia have an increased risk of developing myeloid malignancies including MDS, AML, and CML (PMID: 26693794, PMID: 24030261, PMID: 32618208, PMID: 24628296) but with incomplete penetrance. The proposed mechanism of disease for ANKRD26-related thrombocytopenia (also known as thrombocytopenia 2) is gain-of-function rather than haploinsufficiency (PMIDs: 21211618, 24430186, 28100250).
References:
Marconi et al. 2017 (PMID: 28100250) identified two heterozygous protein-truncating variants in ANKRD26 (c.3G>A/p.Met1? and c.105C>G/p.Tyr35*) in patients with apparently sporadic adult-onset AML. Functional studies showed that both variants produce a slightly shortened ANKRD26 protein with a truncated N-terminus while preserving the downstream sequence. These N-terminal truncated ANKRD26 isoforms are stable and functional in cells and have a strong ability to activate the MAPK/ERK signaling pathway. This study is not being counted as evidence of haploinsufficiency.
Triplosensitivity (TS) Score Details
TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Disease:
- thrombocytopenia 2 Monarch
TS Evidence Comments:
No evidence of triplosensitivity.
While the pathogenesis of thrombocytopenia 2 (THC2) has been linked to the overexpression of ANKRD26, the reported disease-causing variants exert gain-of-function effects (PMIDs: 24430186, 33857290). Focal duplications of ANKRD26 have not been reported in literature. Currently, there is no evidence to support that triplosensitivity of ANKRD26 is a disease-causing mechanism.
References:
Wahlster et al. 2021 (PMID:33857290) identified a complex structural variant (paired-duplication inversion) that segregates with thrombocytopenia in a three-generation family with 9 affected individuals. This inversion leads to the fusion of the promoter and exon 1 of the WAC gene with exons 10-34 of the ANKRD26 gene, resulting in the overexpression of the ANKRD26 C-terminal encoding region and increased MAPK activation. Notably, the duplication within this complex structural variant involves only a portion of the ANKRD26 gene (exons 10-20), which does to result in the copy number gain of entire ANKRD26 gene at the DNA level. The data reported in this study support a gain-of-function mechanism through gene fusion and consequent overexpression of a N-terminally truncated ANKRD26. Therefore, these data are not being counted as evidence of triplosensitivity.
Bluteau et al. 2014 (PMID:24430186) investigated the functional consequences of heterozygous sequence variants in the 5’ UTR of ANKRD26 associated with autosomal dominant thrombocytopenia 2 (THC2). This study showed that these variants disrupt the binding of transcription factors RUNX1 and FLI1 to the 5’ UTR of ANKRD26, resulting in the overexpression of ANKRD26 and hyperactivation of the MAPK/ERK signaling pathway due to the loss of inhibitory regulatory function of RUNX1 and FLI1. The data reported in this study supports a gain-of-function mechanism through the loss of transcription factor binding and, therefore, are not being counted as evidence of triplosensitivity.
Genomic View
Select assembly:
(NC_000010.10)
(NC_000010.11)