rs3729823

chr14-23417200-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000257.4(MYH7):c.4472C>G(p.Ser1491Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,614,158 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (13 hom., cov: 33)
  • Exomes 𝑓: 0.012 (143 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Benign reviewed by expert panel B:24
• Conservation: PhyloP100: 7.79

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]

MHRT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000257.4
• PP2: Missense variant where missense usually causes diseases, MYH7
• BP4: Computational evidence support a benign effect (MetaRNN=0.010740131).
• BP6: Variant 14-23417200-G-C is Benign according to our data. Variant chr14-23417200-G-C is described in ClinVar as [Benign]. Clinvar id is 43020.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-23417200-G-C is described in Lovd as [Likely_pathogenic]. Variant chr14-23417200-G-C is described in Lovd as [Benign]. Variant chr14-23417200-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00854 (1300/152266) while in subpopulation NFE AF= 0.0135 (920/68012). AF 95% confidence interval is 0.0128. There are 13 homozygotes in gnomad4. There are 585 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.4472C>G	p.Ser1491Cys	missense_variant	32/40	ENST00000355349.4
MHRT	NR_126491.1	n.652-12G>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant
MYH7	NM_001407004.1	c.4472C>G	p.Ser1491Cys	missense_variant	31/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.4472C>G	p.Ser1491Cys	missense_variant	32/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes AF: 0.00854 AC: 1299 AN: 152148 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00818 AC: 2058 AN: 251494 Hom.: 16 AF XY: 0.00836 AC XY: 1136 AN XY: 135922

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00639

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00676

Gnomad FIN exome AF: 0.00231

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.00863

GnomAD4 exome AF: 0.0119 AC: 17342 AN: 1461892 Hom.: 143 Cov.: 34 AF XY: 0.0117 AC XY: 8506 AN XY: 727248

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.00704

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00715

Gnomad4 FIN exome AF: 0.00256

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.00929

GnomAD4 genome AF: 0.00854 AC: 1300 AN: 152266 Hom.: 13 Cov.: 33 AF XY: 0.00786 AC XY: 585 AN XY: 74468

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.0135

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0116 Hom.: 6

Bravo AF: 0.00928

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0115 AC: 99

ExAC AF: 0.00746 AC: 906

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0139

ClinVar

Significance: Benign

Submissions summary: Benign:24

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:10

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2012	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. -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 03, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 07, 2016	p.Ser1491Cys in exon 31 of MYH7: This variant is not expected to have clinical s ignificance because it has been identified in 1.1% (698/66740) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs3729823). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 14, 2014	- -

not provided Benign:4

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	Apr 01, 2024	MYH7: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

Hypertrophic cardiomyopathy Benign:3

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -

Cardiomyopathy Benign:2

Benign, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The filtering allele frequency of the c.4472C>G (p.Ser1491Cys) variant in the MYH7 gene is 0.98% (698/66740) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -

Hypertrophic cardiomyopathy 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 12, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Dilated cardiomyopathy 1S Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hypertrophic cardiomyopathy;C0007196:Restrictive cardiomyopathy;C0878544:Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Nov 14, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2015

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
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.40
Sift	Benign	0.035	D
Sift4G	Benign	0.16	T
Polyphen		0.0070	B
Vest4		0.56
MVP		0.94
MPC		0.89
ClinPred		0.044	T
GERP RS		5.3
Varity_R		0.34
gMVP		0.86

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: rs3729823; hg19: chr14-23886409;