Genetic Variant MYH7:c.4520-63G>A (chr14-23417055-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000257.4(MYH7):c.4520-63G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,613,984 control chromosomes in the GnomAD database, including 21,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3302 hom., cov: 32)

Exomes 𝑓: 0.15 ( 18200 hom. )

Consequence

MYH7
NM_000257.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.86

Variant links:

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

MYH7 links:

MHRT (HGNC:51291): (myosin heavy chain associated RNA transcript) This gene encodes a spliced long non-coding RNA that may act as a cardioprotective agent in the heart. Based on a study of a similar gene in mouse, the encoded transcript may regulate chromatin remodeling by acting as a decoy to the BRG1 chromatin repressor complex thus preventing it from binding to its genomic targets. Blocking the actions of BRG1 could be crucial in protecting the heart from pathological hypertrophy. [provided by RefSeq, Dec 2014]

MHRT links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 14-23417055-C-T is Benign according to our data. Variant chr14-23417055-C-T is described in ClinVar as [Benign]. Clinvar id is 1264641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23417055-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.4520-63G>A	intron_variant	Intron 32 of 39	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 link	c.4520-63G>A	intron_variant	Intron 31 of 38		NP_001393933.1
MHRT	NR_126491.1 link	n.651+47C>T	intron_variant	Intron 4 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 link	c.4520-63G>A		intron_variant	Intron 32 of 39	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28303

AN:

152070

Hom.:

3293

Cov.:

show subpopulations

Gnomad AFR

AF:

0.322

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.114

Gnomad ASJ

AF:

0.173

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0422

Gnomad FIN

AF:

0.102

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.159

Gnomad OTH

AF:

0.179

GnomAD4 exome

AF:

0.149

AC:

218065

AN:

1461796

Hom.:

18200

Cov.:

AF XY:

0.146

AC XY:

105968

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.322

Gnomad4 AMR exome

AF:

0.0743

Gnomad4 ASJ exome

AF:

0.174

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0481

Gnomad4 FIN exome

AF:

0.111

Gnomad4 NFE exome

AF:

0.161

Gnomad4 OTH exome

AF:

0.151

GnomAD4 genome

AF:

0.186

AC:

28336

AN:

152188

Hom.:

3302

Cov.:

AF XY:

0.179

AC XY:

13341

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.322

Gnomad4 AMR

AF:

0.114

Gnomad4 ASJ

AF:

0.173

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.0418

Gnomad4 FIN

AF:

0.102

Gnomad4 NFE

AF:

0.159

Gnomad4 OTH

AF:

0.178

Alfa

AF:

0.187

Hom.:

687

Bravo

AF:

0.191

Asia WGS

AF:

0.0410

AC:

145

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy

Benign:1

Sep 27, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.036

DANN

Benign

0.73

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