chr14-23433598-C-A

Position:

• chr14-23433598-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000355349.4(MYH7):​c.135G>T​(p.Glu45Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E45G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH7 ENST00000355349.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.0820

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH7. . Gene score misZ 3.9329 (greater than the threshold 3.09). Trascript score misZ 6.7889 (greater than threshold 3.09). GenCC has associacion of gene with hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.135G>T	p.Glu45Asp	missense_variant	3/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.135G>T	p.Glu45Asp	missense_variant	2/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.135G>T	p.Glu45Asp	missense_variant	3/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 11, 2009

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
CardioboostCm	Benign	0.061
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.021
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.36
Sift	Benign	0.25	T
Sift4G	Uncertain	0.051	T
Polyphen		1.0	D
Vest4		0.39
MutPred		0.30		Gain of catalytic residue at K50 (P = 0.004);
MVP		0.81
MPC		1.7
ClinPred		0.55	D
GERP RS		-0.0077
Varity_R		0.43
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397516102; hg19: chr14-23902807;