rs45580436

Positions:

• chr14-23430884-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000257.4(MYH7):​c.895+17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,586,142 control chromosomes in the GnomAD database, including 515 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (105 hom., cov: 32)
  • Exomes 𝑓: 0.013 (410 hom.)
• Consequence: MYH7 NM_000257.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.11

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 14-23430884-C-T is Benign according to our data. Variant chr14-23430884-C-T is described in ClinVar as [Benign]. Clinvar id is 188603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23430884-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.895+17G>A		intron_variant		ENST00000355349.4
MYH7	NM_001407004.1	c.895+17G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.895+17G>A		intron_variant		1	NM_000257.4	P1

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3767 AN: 152060 Hom.: 104 Cov.: 32

Gnomad AFR AF: 0.0468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0287

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.0749

Gnomad SAS AF: 0.0382

Gnomad FIN AF: 0.00604

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.00773

Gnomad OTH AF: 0.0416

GnomAD3 exomes AF: 0.0241 AC: 6052 AN: 251438 Hom.: 166 AF XY: 0.0232 AC XY: 3146 AN XY: 135888

Gnomad AFR exome AF: 0.0506

Gnomad AMR exome AF: 0.0383

Gnomad ASJ exome AF: 0.0259

Gnomad EAS exome AF: 0.0734

Gnomad SAS exome AF: 0.0360

Gnomad FIN exome AF: 0.00559

Gnomad NFE exome AF: 0.00804

Gnomad OTH exome AF: 0.0252

GnomAD4 exome AF: 0.0129 AC: 18482 AN: 1433964 Hom.: 410 Cov.: 30 AF XY: 0.0134 AC XY: 9596 AN XY: 715172

Gnomad4 AFR exome AF: 0.0546

Gnomad4 AMR exome AF: 0.0371

Gnomad4 ASJ exome AF: 0.0286

Gnomad4 EAS exome AF: 0.0838

Gnomad4 SAS exome AF: 0.0344

Gnomad4 FIN exome AF: 0.00500

Gnomad4 NFE exome AF: 0.00575

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0248 AC: 3780 AN: 152178 Hom.: 105 Cov.: 32 AF XY: 0.0251 AC XY: 1865 AN XY: 74400

Gnomad4 AFR AF: 0.0469

Gnomad4 AMR AF: 0.0288

Gnomad4 ASJ AF: 0.0331

Gnomad4 EAS AF: 0.0751

Gnomad4 SAS AF: 0.0380

Gnomad4 FIN AF: 0.00604

Gnomad4 NFE AF: 0.00773

Gnomad4 OTH AF: 0.0454

Alfa AF: 0.0180 Hom.: 9

Bravo AF: 0.0287

Asia WGS AF: 0.0810 AC: 283 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hypertrophic cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2014

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	-0.91
CADD	Benign	0.24
DANN	Benign	0.49

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

Other links and lift over

dbSNP: rs45580436; hg19: chr14-23900093; COSMIC: COSV62517513;