rs145508517

Positions:

• chr14-23392964-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_002471.4(MYH6):​c.3199A>G​(p.Ser1067Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,614,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 1.40

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 -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH6
• BP4: Computational evidence support a benign effect (MetaRNN=0.13693443).
• BP6: Variant 14-23392964-T-C is Benign according to our data. Variant chr14-23392964-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44477.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}.
• BS2: High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.3199A>G	p.Ser1067Gly	missense_variant	24/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.3199A>G	p.Ser1067Gly	missense_variant	24/39	5	NM_002471.4	P1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000596 AC: 15 AN: 251494 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135922

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727248

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74464

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000727 Hom.: 0

Bravo AF: 0.000287

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 28, 2019	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2021	Has not been previously published in association with an MYH6-related disorder to our knowledge; Reported in ClinVar (ClinVar Variant ID# 44477; Landrum 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: 23861362) -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 22, 2017	Variant classified as Uncertain Significance - Favor Benign. The p.Ser1067Gly va riant in MYH6 has been identified by our laboratory in 1 Hispanic individual wit h HCM, but did NOT segregate with disease in 1 affected relative. This variant w as identified in 0.1% (11/10406) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs145508517). Computat ional prediction tools and conservation analysis do not provide strong support f or or against an impact to the protein. This variant was identified in ClinVar ( Variant ID:44477). In summary, while the clinical significance of the p.Ser1067G ly variant is uncertain, its frequency and non-segregation suggests that it is m ore likely to be benign. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 29, 2018	Variant summary: MYH6 c.3199A>G (p.Ser1067Gly) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant frequency in the gnomAD database was 0.000097, but was observed predominantly in the African subpopulation at a frequency of 0.00099. This frequency within African control individuals in the gnomAD database is approximately 40 fold above the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.3199A>G has been reported in the literature, however, this report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as uncertain significance, although the summary evidence provided by one of them suggests a benign etiology. Based on the evidence outlined above, the variant was classified as likely benign. -

Hypertrophic cardiomyopathy 14 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.090
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.83	T;.
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.0010	B;B
Vest4		0.55
MVP		0.92
MPC		0.32
ClinPred		0.28	T
GERP RS		4.8
Varity_R		0.77
gMVP		0.28

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: rs145508517; hg19: chr14-23862173; COSMIC: COSV62452199; COSMIC: COSV62452199;