rs373457153

Variant names:

• chr14-23386014-C-A
• rs373457153
• NM_002471.4:c.5077G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-23386014-C-A
• chr14-23386014-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002471.4(MYH6):​c.5077G>T​(p.Val1693Leu) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1693M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.0190

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.105697036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4	c.5077G>T	p.Val1693Leu	missense_variant	Exon 34 of 39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.5077G>T	p.Val1693Leu	missense_variant	Exon 34 of 39	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

MYH6-related disorder Uncertain:1

Jul 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MYH6 c.5077G>T variant is predicted to result in the amino acid substitution p.Val1693Leu. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.0
DANN	Benign	0.93
DEOGEN2	Benign	0.36	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.73	T;.
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.48	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.53	N;N
REVEL	Benign	0.17
Sift	Benign	0.39	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.0	B;B
Vest4		0.14
MutPred		0.42		Loss of phosphorylation at T1697 (P = 0.2156);Loss of phosphorylation at T1697 (P = 0.2156);
MVP		0.54
MPC		0.25
ClinPred		0.12	T
GERP RS		1.3
Varity_R		0.026
gMVP		0.18

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

Other links and lift over

dbSNP: rs373457153; hg19: chr14-23855223;