rs34855944

Positions:

chr14-23387652-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_002471.4(MYH6):c.4527G>A(p.Glu1509=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00873 in 1,614,074 control chromosomes in the GnomAD database, including 262 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 125 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 137 hom. )

Consequence

MYH6
NM_002471.4 splice_region, synonymous

Scores

Splicing: ADA: 0.02693

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 4.77

Variant links:

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]

MYH6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.19).

BP6

Variant 14-23387652-C-T is Benign according to our data. Variant chr14-23387652-C-T is described in ClinVar as [Benign]. Clinvar id is 44515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23387652-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.4527G>A	p.Glu1509=	splice_region_variant, synonymous_variant	32/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9 linkuse as main transcript	c.4527G>A	p.Glu1509=	splice_region_variant, synonymous_variant	32/39	5	NM_002471.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3815

AN:

152078

Hom.:

125

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0766

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00910

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.0164

Gnomad SAS

AF:

0.00581

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00501

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.0101

AC:

2548

AN:

251488

Hom.:

AF XY:

0.00861

AC XY:

1170

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0796

Gnomad AMR exome

AF:

0.00743

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.0166

Gnomad SAS exome

AF:

0.00510

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00404

Gnomad OTH exome

AF:

0.00863

GnomAD4 exome

AF:

0.00702

AC:

10261

AN:

1461878

Hom.:

137

Cov.:

AF XY:

0.00664

AC XY:

4829

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0737

Gnomad4 AMR exome

AF:

0.00812

Gnomad4 ASJ exome

AF:

0.00138

Gnomad4 EAS exome

AF:

0.0126

Gnomad4 SAS exome

AF:

0.00572

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.00515

Gnomad4 OTH exome

AF:

0.0102

GnomAD4 genome

AF:

0.0251

AC:

3823

AN:

152196

Hom.:

125

Cov.:

AF XY:

0.0243

AC XY:

1809

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0766

Gnomad4 AMR

AF:

0.00908

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.0165

Gnomad4 SAS

AF:

0.00581

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00501

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.00928

Hom.:

Bravo

AF:

0.0282

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.00534

EpiControl

AF:

0.00421

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 24, 2012	7.3% (273/3738) of Afr Amer chrom in ESP -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hypertrophic cardiomyopathy 14

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2023

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2015

This alteration is classified as 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

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.027

dbscSNV1_RF

Benign

0.17

SpliceAI score (max)

0.79

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.79

Position offset: -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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over