NM_000257.4:c.*143C>A

Variant names:

• chr14-23412711-G-T
• rs12147570
• NM_000257.4:c.*143C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000257.4(MYH7):​c.*143C>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 977,046 control chromosomes in the GnomAD database, including 10,096 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1362 hom., cov: 32)
  • Exomes 𝑓: 0.14 (8734 hom.)
• Consequence: MYH7 NM_000257.4 downstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.364
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1S

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• MYH7-related skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• myopathy, myosin storage, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myopathy, myosin storage, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital myopathy 7A, myosin storage, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ebstein anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyaline body myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.*143C>A		downstream_gene_variant		ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.*143C>A		downstream_gene_variant			NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.*143C>A		downstream_gene_variant		1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.*192C>A		downstream_gene_variant				ENSP00000519070.1
MYH7	ENST00000713769.1	c.*143C>A		downstream_gene_variant				ENSP00000519071.1

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19377 AN: 152078 Hom.: 1360 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0910

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0408

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.132

GnomAD4 exome AF: 0.136 AC: 112067 AN: 824850 Hom.: 8734 Cov.: 11 AF XY: 0.132 AC XY: 56659 AN XY: 427936

African (AFR) AF: 0.120 AC: 2511 AN: 21012

American (AMR) AF: 0.0640 AC: 2280 AN: 35640

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 3630 AN: 21038

East Asian (EAS) AF: 0.0000588 AC: 2 AN: 34040

South Asian (SAS) AF: 0.0474 AC: 3181 AN: 67056

European-Finnish (FIN) AF: 0.112 AC: 4229 AN: 37678

Middle Eastern (MID) AF: 0.0902 AC: 303 AN: 3358

European-Non Finnish (NFE) AF: 0.160 AC: 90592 AN: 565600

Other (OTH) AF: 0.135 AC: 5339 AN: 39428

GnomAD4 genome AF: 0.127 AC: 19395 AN: 152196 Hom.: 1362 Cov.: 32 AF XY: 0.124 AC XY: 9208 AN XY: 74424

African (AFR) AF: 0.120 AC: 4993 AN: 41516

American (AMR) AF: 0.0910 AC: 1392 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 596 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0404 AC: 195 AN: 4828

European-Finnish (FIN) AF: 0.102 AC: 1080 AN: 10596

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10746 AN: 67990

Other (OTH) AF: 0.131 AC: 276 AN: 2110

Alfa AF: 0.141 Hom.: 3059

Bravo AF: 0.125

Asia WGS AF: 0.0290 AC: 103 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		0.36
Mutation Taster		=98/2	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12147570; hg19: chr14-23881920;