NM_000257.4:c.2945T>C

Variant names:

• chr14-23423701-A-G
• rs145532615
• NM_000257.4:c.2945T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.2945T>C (p.Met982Thr) variant in the MYH7 gene is 0.11% (88/66740) 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA013227/MONDO:0004994/002

• Frequency:
  • Genomes: 𝑓 0.00093 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (6 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:19
• Conservation: PhyloP100: 9.09
• Publications: 20 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

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

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

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• 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 -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000257.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.2945T>C	p.Met982Thr	missense	Exon 24 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.2945T>C	p.Met982Thr	missense	Exon 23 of 39	NP_001393933.1	P12883

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.2945T>C	p.Met982Thr	missense	Exon 24 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.2945T>C	p.Met982Thr	missense	Exon 24 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.2945T>C	p.Met982Thr	missense	Exon 24 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.000927 AC: 141 AN: 152040 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000850

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000839 AC: 211 AN: 251492 AF XY: 0.000809

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.00174 AC: 2545 AN: 1461868 Hom.: 6 Cov.: 35 AF XY: 0.00164 AC XY: 1196 AN XY: 727236

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000545 AC: 47 AN: 86258

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00215 AC: 2386 AN: 1111990

Other (OTH) AF: 0.00118 AC: 71 AN: 60396

GnomAD4 genome AF: 0.000927 AC: 141 AN: 152158 Hom.: 1 Cov.: 32 AF XY: 0.000753 AC XY: 56 AN XY: 74360

African (AFR) AF: 0.000337 AC: 14 AN: 41518

American (AMR) AF: 0.000327 AC: 5 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.000850 AC: 9 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00159 AC: 108 AN: 68008

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.000888

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.000906 AC: 110

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)
-	-	3	Cardiomyopathy (3)
-	1	2	not provided (3)
-	1	1	Increased left ventricular wall thickness (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy (1)
-	-	1	Dilated cardiomyopathy 1S (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 1 (1)
-	-	1	Left ventricular noncompaction (1)
-	-	1	MYH7-related disorder (1)
-	-	1	MYH7-related skeletal myopathy (1)
-	-	1	Myosin storage myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
CardioboostCm	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.027	D
Polyphen		0.98	D
Vest4		0.97
MVP		0.98
MPC		1.2
ClinPred		0.049	T
GERP RS		5.1
Varity_R		0.71
gMVP		0.99
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs145532615; hg19: chr14-23892910;