chr10-90918869-T-C
Variant summary
Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3
The NM_014391.3(ANKRD1):c.449A>G(p.Asp150Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000249 in 1,608,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D150V) has been classified as Likely benign.
Frequency
Consequence
NM_014391.3 missense
Scores
Clinical Significance
Conservation
Publications
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- dilated cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- hypertrophic cardiomyopathyInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ANKRD1 | NM_014391.3 | c.449A>G | p.Asp150Gly | missense_variant | Exon 4 of 9 | ENST00000371697.4 | NP_055206.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151800Hom.: 0 Cov.: 30 show subpopulations
GnomAD2 exomes AF: 0.00000400 AC: 1AN: 250284 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1456794Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 725092 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151800Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 74140 show subpopulations
ClinVar
Submissions by phenotype
ANKRD1-related dilated cardiomyopathy Uncertain:1
This sequence change replaces aspartic acid with glycine at codon 150 of the ANKRD1 protein (p.Asp150Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs150266349, ExAC 0.002%). This variant has not been reported in the literature in individuals with ANKRD1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Cardiovascular phenotype Uncertain:1
The p.D150G variant (also known as c.449A>G), located in coding exon 4 of the ANKRD1 gene, results from an A to G substitution at nucleotide position 449. The aspartic acid at codon 150 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at