chr10-90918901-G-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_014391.3(ANKRD1):c.417C>A(p.Phe139Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,611,948 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_014391.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ANKRD1 | NM_014391.3 | c.417C>A | p.Phe139Leu | missense_variant | Exon 4 of 9 | ENST00000371697.4 | NP_055206.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000416 AC: 63AN: 151410Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.000523 AC: 131AN: 250530Hom.: 0 AF XY: 0.000458 AC XY: 62AN XY: 135464
GnomAD4 exome AF: 0.000240 AC: 351AN: 1460426Hom.: 2 Cov.: 31 AF XY: 0.000250 AC XY: 182AN XY: 726594
GnomAD4 genome AF: 0.000416 AC: 63AN: 151522Hom.: 0 Cov.: 30 AF XY: 0.000621 AC XY: 46AN XY: 74038
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Variant classified as Uncertain Significance - Favor Benign. The Phe139Leu varia nt in ANKRD1 has been identified by our laboratory in one individual with DCM, b ut did not segregate with disease in 1 affected relative. In addition, this vari ant has been identified in 1/186 Finnish chromosomes by the 1000 Genomes Sequenc ing Project (http://1000genomes.org; dbSNP rs201398260), though this could repre sent a presymptomatic individual. Phenylalanine (Phe) at this position is not co nserved in mammals or evolutionarily distant species, suggesting that a change a t this position may be tolerated. Additional computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong su pport for or against an impact to the protein. Although this data supports that the Phe139Leu variant may be benign, additional studies are needed to fully asse ss its clinical significance. -
Variant summary: ANKRD1 c.417C>A (p.Phe139Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 250530 control chromosomes (gnomAD). The observed variant frequency is approximately 21-fold of the estimated maximal expected allele frequency for a pathogenic variant in ANKRD1 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.417C>A has been reported in the literature as a VUS in settings of multigene panel testing in an individual affected with Dilated Cardiomyopathy and in cases of sudden cardiac death, without strong evidence for causality (e.g. Pugh_2014, Hertz_2016, Vahatalo_2021). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26383259, 24503780, 35087879). ClinVar contains an entry for this variant (Variation ID: 45634). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided Uncertain:1
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26383259) -
Cardiomyopathy Benign:1
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ANKRD1-related dilated cardiomyopathy Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at