14-23386553-A-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_002471.4(MYH6):c.4721T>A(p.Ile1574Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,338 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.4721T>A | p.Ile1574Asn | missense_variant | Exon 33 of 39 | ENST00000405093.9 | NP_002462.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151444Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251400Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135872
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461778Hom.: 0 Cov.: 71 AF XY: 0.0000124 AC XY: 9AN XY: 727178
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151560Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2AN XY: 74000
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 14 Uncertain:1
In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is present in population databases (rs199627411, ExAC 0.01%) but has not been reported in the literature in individuals with a MYH6-related disease. This sequence change replaces isoleucine with asparagine at codon 1574 of the MYH6 protein (p.Ile1574Asn). The isoleucine residue is weakly conserved and there is a large physicochemical difference between isoleucine and asparagine. -
Cardiovascular phenotype Uncertain:1
The p.I1574N variant (also known as c.4721T>A), located in coding exon 31 of the MYH6 gene, results from a T to A substitution at nucleotide position 4721. The isoleucine at codon 1574 is replaced by asparagine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. 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