Genetic Variant MYH6:c.3979-7T>C (chr14-23389062-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_002471.4(MYH6):c.3979-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 7 hom., cov: 26)

Exomes 𝑓: 0.016 ( 5 hom. )

Failed GnomAD Quality Control

Consequence

MYH6
NM_002471.4 splice_region, intron

Scores

Splicing: ADA: 0.00006140

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 14-23389062-A-G is Benign according to our data. Variant chr14-23389062-A-G is described in ClinVar as [Benign]. Clinvar id is 239170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23389062-A-G is described in Lovd as [Benign]. Variant chr14-23389062-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4 link	c.3979-7T>C		splice_region_variant, intron_variant	Intron 28 of 38	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9 link	c.3979-7T>C		splice_region_variant, intron_variant	Intron 28 of 38	5	NM_002471.4	ENSP00000386041.3		P13533

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

1752

AN:

115424

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0155

Gnomad AMI

AF:

0.0133

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.0120

Gnomad EAS

AF:

0.0145

Gnomad SAS

AF:

0.00992

Gnomad FIN

AF:

0.0148

Gnomad MID

AF:

0.00775

Gnomad NFE

AF:

0.0168

Gnomad OTH

AF:

0.0140

GnomAD3 exomes

AF:

0.0589

AC:

8229

AN:

139674

Hom.:

AF XY:

0.0582

AC XY:

4436

AN XY:

76278

show subpopulations

Gnomad AFR exome

AF:

0.0175

Gnomad AMR exome

AF:

0.0803

Gnomad ASJ exome

AF:

0.0509

Gnomad EAS exome

AF:

0.0708

Gnomad SAS exome

AF:

0.0353

Gnomad FIN exome

AF:

0.0594

Gnomad NFE exome

AF:

0.0668

Gnomad OTH exome

AF:

0.0588

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0162

AC:

17102

AN:

1053674

Hom.:

Cov.:

AF XY:

0.0180

AC XY:

9439

AN XY:

524690

show subpopulations

Gnomad4 AFR exome

AF:

0.0164

Gnomad4 AMR exome

AF:

0.0685

Gnomad4 ASJ exome

AF:

0.0221

Gnomad4 EAS exome

AF:

0.0209

Gnomad4 SAS exome

AF:

0.0465

Gnomad4 FIN exome

AF:

0.0434

Gnomad4 NFE exome

AF:

0.0103

Gnomad4 OTH exome

AF:

0.0177

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0152

AC:

1751

AN:

115534

Hom.:

Cov.:

AF XY:

0.0135

AC XY:

767

AN XY:

56790

show subpopulations

Gnomad4 AFR

AF:

0.0155

Gnomad4 AMR

AF:

0.0103

Gnomad4 ASJ

AF:

0.0120

Gnomad4 EAS

AF:

0.0145

Gnomad4 SAS

AF:

0.00992

Gnomad4 FIN

AF:

0.0148

Gnomad4 NFE

AF:

0.0168

Gnomad4 OTH

AF:

0.0138

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 08, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Jun 20, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MYH6 c.3979-7T>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing and ESEfinder predicts changes of binding motifs for RNA splicing enhancers. This variant was found in 267/76776 control chromosomes (2 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0154313 (122/7906). This frequency is about 617 times the estimated maximal expected allele frequency of a pathogenic MYH6 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications or clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 14

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Benign:1

Dec 12, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

2.5

DANN

Benign

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000061

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.020

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