rs397516195

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_000257.4(MYH7):​c.3830G>T​(p.Arg1277Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Consequence

MYH7
NM_000257.4 missense

Scores

4
12
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.87
Variant links:
Genes affected
MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the MYH7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.9329 (above the threshold of 3.09). Trascript score misZ: 6.7889 (above the threshold of 3.09). GenCC associations: The gene is linked to hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH7NM_000257.4 linkc.3830G>T p.Arg1277Leu missense_variant Exon 28 of 40 ENST00000355349.4 NP_000248.2 P12883
MYH7NM_001407004.1 linkc.3830G>T p.Arg1277Leu missense_variant Exon 27 of 39 NP_001393933.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH7ENST00000355349.4 linkc.3830G>T p.Arg1277Leu missense_variant Exon 28 of 40 1 NM_000257.4 ENSP00000347507.3 P12883

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
44
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
CardioboostCm
Uncertain
0.46
BayesDel_addAF
Uncertain
0.056
T
BayesDel_noAF
Benign
-0.16
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
D
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
0.86
D
MetaSVM
Uncertain
0.19
D
MutationAssessor
Uncertain
2.3
M
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-4.5
D
REVEL
Uncertain
0.61
Sift
Uncertain
0.0010
D
Sift4G
Benign
0.45
T
Polyphen
0.73
P
Vest4
0.66
MutPred
0.53
Loss of MoRF binding (P = 0.0421);
MVP
0.94
MPC
1.6
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.52
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397516195; hg19: chr14-23888715; API