chr14-23383311-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_002471.4(MYH6):c.5575G>A(p.Asp1859Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000194 in 103,156 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 (★★).
Frequency
Consequence
NM_002471.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.5575G>A | p.Asp1859Asn | missense_variant | Exon 37 of 39 | ENST00000405093.9 | NP_002462.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000194 AC: 2AN: 103156Hom.: 0 Cov.: 22
GnomAD3 exomes AF: 0.00000429 AC: 1AN: 233300Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 126894
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000194 AC: 11AN: 566824Hom.: 0 Cov.: 30 AF XY: 0.0000171 AC XY: 5AN XY: 292630
GnomAD4 genome AF: 0.0000194 AC: 2AN: 103156Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 46512
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 14 Uncertain:1
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1859 of the MYH6 protein (p.Asp1859Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 470550). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH6 protein function. 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. -
not provided Uncertain:1
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Cardiovascular phenotype Uncertain:1
The p.D1859N variant (also known as c.5575G>A), located in coding exon 35 of the MYH6 gene, results from a G to A substitution at nucleotide position 5575. The aspartic acid at codon 1859 is replaced by asparagine, an amino acid with highly 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