rs776853139
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2
The NM_002471.4(MYH6):c.421G>A(p.Ala141Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000378 in 1,614,044 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
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )
Consequence
MYH6
NM_002471.4 missense
NM_002471.4 missense
Scores
4
11
4
Clinical Significance
Conservation
PhyloP100: 5.92
Genes affected
MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, MYH6
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.855
BS2
?
High AC in GnomAd4 at 12 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.421G>A | p.Ala141Thr | missense_variant | 5/39 | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.421G>A | p.Ala141Thr | missense_variant | 5/39 | 5 | NM_002471.4 | P1 | |
MYH6 | ENST00000557461.2 | n.488G>A | non_coding_transcript_exon_variant | 5/14 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152222Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251488Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135916
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GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461822Hom.: 0 Cov.: 34 AF XY: 0.0000316 AC XY: 23AN XY: 727210
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GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74368
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 20, 2020 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31983221) - |
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Hypertrophic cardiomyopathy 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 18, 2023 | 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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt MYH6 protein function. ClinVar contains an entry for this variant (Variation ID: 191722). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). This variant is present in population databases (rs776853139, gnomAD 0.005%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 141 of the MYH6 protein (p.Ala141Thr). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 07, 2023 | The p.A141T variant (also known as c.421G>A), located in coding exon 3 of the MYH6 gene, results from a G to A substitution at nucleotide position 421. The alanine at codon 141 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort and was also noted in a healthy control (Mazzarotto F et al. Circulation, 2020 Feb;141:387-398). This alteration has also been reported as a secondary cardiac variant in an exome cohort; however, clinical details are limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Benign
T;T
Polyphen
D;D
Vest4
MutPred
Gain of catalytic residue at R143 (P = 0.0017);Gain of catalytic residue at R143 (P = 0.0017);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at