14-23416151-G-T

Variant names:

• chr14-23416151-G-T
• rs142034311
• NM_000257.4:c.4806C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_000257.4(MYH7):​c.4806C>A​(p.Asp1602Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D1602D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.95
• Publications: 0 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]

MHRT (HGNC:51291): (myosin heavy chain associated RNA transcript) This gene encodes a spliced long non-coding RNA that may act as a cardioprotective agent in the heart. Based on a study of a similar gene in mouse, the encoded transcript may regulate chromatin remodeling by acting as a decoy to the BRG1 chromatin repressor complex thus preventing it from binding to its genomic targets. Blocking the actions of BRG1 could be crucial in protecting the heart from pathological hypertrophy. [provided by RefSeq, Dec 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 uncertain in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MYH7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.9329 (above the threshold of 3.09). Trascript score misZ: 6.7889 (above the threshold of 3.09). GenCC associations: The gene is linked to myopathy, myosin storage, autosomal recessive, MYH7-related skeletal myopathy, congenital myopathy 7A, myosin storage, autosomal dominant, Ebstein anomaly, hyaline body myopathy, left ventricular noncompaction, hypertrophic cardiomyopathy 1, dilated cardiomyopathy 1S, dilated cardiomyopathy, congenital heart disease, familial isolated dilated cardiomyopathy, myopathy, myosin storage, autosomal dominant, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21957463).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.4806C>A	p.Asp1602Glu	missense	Exon 34 of 40	NP_000248.2
	MYH7	NM_001407004.1		c.4806C>A	p.Asp1602Glu	missense	Exon 33 of 39	NP_001393933.1
	MHRT	NR_126491.1		n.412G>T		non_coding_transcript_exon	Exon 3 of 6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.4806C>A	p.Asp1602Glu	missense	Exon 34 of 40	ENSP00000347507.3
	MYH7	ENST00000713768.1		c.4806C>A	p.Asp1602Glu	missense	Exon 34 of 41	ENSP00000519070.1
	MYH7	ENST00000713769.1		c.4806C>A	p.Asp1602Glu	missense	Exon 33 of 39	ENSP00000519071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459914 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726346

African (AFR) AF: 0.00 AC: 0 AN: 32950

American (AMR) AF: 0.00 AC: 0 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110948

Other (OTH) AF: 0.00 AC: 0 AN: 60274

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiomyopathy Uncertain:1

Apr 10, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with glutamic acid at codon 1602 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH7-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
CardioboostCm	Uncertain	0.22
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.0010
DANN	Benign	0.86
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.45	N
PhyloP100		-4.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.17
Sift	Benign	0.15	T
Sift4G	Benign	0.98	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.43		Loss of MoRF binding (P = 0.1267)
MVP		0.40
MPC		0.83
ClinPred		0.086	T
GERP RS		-5.5
Varity_R		0.17
gMVP		0.44
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: rs142034311; hg19: chr14-23885360;