Genetic Variant MYH6:c.3979-8C>A (chr14-23389063-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_002471.4(MYH6):c.3979-8C>A 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0050 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MYH6
NM_002471.4 splice_region, intron

Scores

Splicing: ADA: 0.001567

Clinical Significance

Likely benign criteria provided, single submitter B:4

Conservation

PhyloP100: 0.275

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 14-23389063-G-T is Benign according to our data. Variant chr14-23389063-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1285119.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23389063-G-T 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.3979-8C>A		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.3979-8C>A		splice_region_variant, intron_variant	Intron 28 of 38	5	NM_002471.4	ENSP00000386041.3		P13533

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

64966

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00310

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000235

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00148

Gnomad SAS

AF:

0.00240

Gnomad FIN

AF:

0.000160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000284

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000589

AC:

AN:

152678

Hom.:

AF XY:

0.0000719

AC XY:

AN XY:

83470

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000661

Gnomad SAS exome

AF:

0.0000538

Gnomad FIN exome

AF:

0.0000913

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00496

AC:

2134

AN:

430598

Hom.:

Cov.:

AF XY:

0.00485

AC XY:

1022

AN XY:

210514

show subpopulations

Gnomad4 AFR exome

AF:

0.0420

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00457

Gnomad4 EAS exome

AF:

0.00325

Gnomad4 SAS exome

AF:

0.00255

Gnomad4 FIN exome

AF:

0.00113

Gnomad4 NFE exome

AF:

0.00436

Gnomad4 OTH exome

AF:

0.00630

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000493

AC:

AN:

64950

Hom.:

Cov.:

AF XY:

0.000374

AC XY:

AN XY:

32108

show subpopulations

Gnomad4 AFR

AF:

0.00292

Gnomad4 AMR

AF:

0.000234

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00149

Gnomad4 SAS

AF:

0.00241

Gnomad4 FIN

AF:

0.000160

Gnomad4 NFE

AF:

0.0000284

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 14

Benign:1

Feb 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MYH6-related disorder

Benign:1

Mar 19, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

3.8

DANN

Benign

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0016

dbscSNV1_RF

Benign

0.034

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