rs769554911

chr14-23390263-T-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_002471.4(MYH6):c.3526A>T(p.Met1176Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000486 in 1,439,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74

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 Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH6
• BP4: Computational evidence support a benign effect (MetaRNN=0.16217434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.3526A>T	p.Met1176Leu	missense_variant	26/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.3526A>T	p.Met1176Leu	missense_variant	26/39	5	NM_002471.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000180 AC: 4 AN: 221620 Hom.: 0 AF XY: 0.0000247 AC XY: 3 AN XY: 121680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000102

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000182

GnomAD4 exome AF: 0.00000486 AC: 7 AN: 1439370 Hom.: 0 Cov.: 34 AF XY: 0.00000840 AC XY: 6 AN XY: 714364

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000705

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000844 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy 14 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 01, 2016

In summary, this variant is a rare missense change with uncertain impact on protein function. It is not expected to cause 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"). While this variant is present in population databases (rs769554911), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a MYH6-related disease. This sequence change replaces methionine with leucine at codon 1176 of the MYH6 protein (p.Met1176Leu). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	20
Dann	Benign	0.96
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T;.
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.5	N;N
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.030	N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.41
MutPred		0.39		Gain of methylation at K1175 (P = 0.0323);Gain of methylation at K1175 (P = 0.0323);
MVP		0.56
MPC		1.6
ClinPred		0.14	T
GERP RS		4.2
Varity_R		0.14
gMVP		0.44

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: rs769554911; hg19: chr14-23859472;