rs78107039

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002471.4(MYH6):c.999C>T(p.Thr333=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,613,290 control chromosomes in the GnomAD database, including 497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 223 hom., cov: 30)

Exomes 𝑓: 0.011 ( 274 hom. )

Consequence

MYH6
NM_002471.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -7.33

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 14-23402700-G-A is Benign according to our data. Variant chr14-23402700-G-A is described in ClinVar as [Benign]. Clinvar id is 36634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23402700-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-7.33 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.999C>T	p.Thr333=	synonymous_variant	11/39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9 linkuse as main transcript	c.999C>T	p.Thr333=	synonymous_variant	11/39	5	NM_002471.4	ENSP00000386041	P1
MYH6	ENST00000557461.2 linkuse as main transcript	n.1066C>T		non_coding_transcript_exon_variant	11/14	5

Frequencies

GnomAD3 genomes

AF:

0.0344

AC:

5213

AN:

151346

Hom.:

222

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0977

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0263

Gnomad ASJ

AF:

0.0231

Gnomad EAS

AF:

0.000596

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.0000949

Gnomad MID

AF:

0.0224

Gnomad NFE

AF:

0.00744

Gnomad OTH

AF:

0.0409

GnomAD3 exomes

AF:

0.0183

AC:

4597

AN:

251260

Hom.:

130

AF XY:

0.0175

AC XY:

2378

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.0193

Gnomad ASJ exome

AF:

0.0290

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0260

Gnomad FIN exome

AF:

0.000509

Gnomad NFE exome

AF:

0.00929

Gnomad OTH exome

AF:

0.0217

GnomAD4 exome

AF:

0.0110

AC:

16064

AN:

1461826

Hom.:

274

Cov.:

AF XY:

0.0114

AC XY:

8303

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0936

Gnomad4 AMR exome

AF:

0.0199

Gnomad4 ASJ exome

AF:

0.0259

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0264

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.00683

Gnomad4 OTH exome

AF:

0.0192

GnomAD4 genome

AF:

0.0345

AC:

5227

AN:

151464

Hom.:

223

Cov.:

AF XY:

0.0334

AC XY:

2469

AN XY:

74002

show subpopulations

Gnomad4 AFR

AF:

0.0976

Gnomad4 AMR

AF:

0.0262

Gnomad4 ASJ

AF:

0.0231

Gnomad4 EAS

AF:

0.000598

Gnomad4 SAS

AF:

0.0238

Gnomad4 FIN

AF:

0.0000949

Gnomad4 NFE

AF:

0.00744

Gnomad4 OTH

AF:

0.0438

Alfa

AF:

0.0148

Hom.:

Bravo

AF:

0.0377

Asia WGS

AF:

0.0290

AC:

102

AN:

3478

EpiCase

AF:

0.0114

EpiControl

AF:

0.0127

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Apr 25, 2012	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hypertrophic cardiomyopathy 14

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiomyopathy

Benign:1

Benign, no assertion criteria provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 20, 2011

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 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

-0.89

CADD

Benign

1.9

DANN

Benign

0.94

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.

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