rs545343612

chr14-23389061-GA-GAAchr14-23389061-GA-GGC

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_002471.4(MYH6):c.3979-7_3979-6insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 123,168 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 26)

Exomes 𝑓: 0.0024 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

MYH6
NM_002471.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.588

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 -12 ACMG points.

BP6

Variant 14-23389061-G-GA is Benign according to our data. Variant chr14-23389061-G-GA is described in ClinVar as [Likely_benign]. Clinvar id is 179076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd at 243 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.3979-7_3979-6insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9 linkuse as main transcript	c.3979-7_3979-6insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_002471.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00197

AC:

243

AN:

123096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.000324

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000202

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00271

Gnomad OTH

AF:

0.00284

GnomAD3 exomes

AF:

0.00189

AC:

349

AN:

184810

Hom.:

AF XY:

0.00180

AC XY:

182

AN XY:

101172

show subpopulations

Gnomad AFR exome

AF:

0.000895

Gnomad AMR exome

AF:

0.00434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000230

Gnomad FIN exome

AF:

0.0000723

Gnomad NFE exome

AF:

0.00232

Gnomad OTH exome

AF:

0.00220

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00239

AC:

3275

AN:

1367802

Hom.:

Cov.:

AF XY:

0.00235

AC XY:

1597

AN XY:

679218

show subpopulations

Gnomad4 AFR exome

AF:

0.000379

Gnomad4 AMR exome

AF:

0.00373

Gnomad4 ASJ exome

AF:

0.0000422

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.000132

Gnomad4 FIN exome

AF:

0.0000835

Gnomad4 NFE exome

AF:

0.00290

Gnomad4 OTH exome

AF:

0.00142

GnomAD4 genome

AF:

0.00197

AC:

243

AN:

123168

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

114

AN XY:

60500

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.00313

Gnomad4 ASJ

AF:

0.000324

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000202

Gnomad4 NFE

AF:

0.00271

Gnomad4 OTH

AF:

0.00281

Bravo

AF:

0.00206

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	MYH6: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2016	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 17, 2013	3979-7_3979-6insT in intron 28 of MYH6: This variant is not expected to have cli nical significance because it has been identified in 1.9% (78/4188) of African A merican chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washing ton.edu/EVS/). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 30, 2018	Variant summary: MYH6 c.3979-7dupT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0018 in 205828 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 72 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3979-7dupT in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy 14

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Oct 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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