rs2754155

Variant names:

• chr14-23416946-A-G
• rs2754155
• NM_000257.4:c.4566T>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.4566T>C (p.Thr1522=) variant in the MYH7 gene is 2.98% (376/11574) of Latino 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/CA015116/MONDO:0004994/002

• Frequency:
  • Genomes: 𝑓 0.0089 (16 hom., cov: 33)
  • Exomes 𝑓: 0.0095 (132 hom.)
• Consequence: MYH7 NM_000257.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:21
• Conservation: PhyloP100: -0.423
• Publications: 3 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: 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.4566T>C	p.Thr1522Thr	synonymous	Exon 33 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.4566T>C	p.Thr1522Thr	synonymous	Exon 32 of 39	NP_001393933.1	P12883
	MHRT	NR_126491.1		n.589A>G		non_coding_transcript_exon	Exon 4 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.4566T>C	p.Thr1522Thr	synonymous	Exon 33 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.4566T>C	p.Thr1522Thr	synonymous	Exon 33 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.4566T>C	p.Thr1522Thr	synonymous	Exon 33 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.00893 AC: 1360 AN: 152212 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0174

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0265

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00967

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0134 AC: 3367 AN: 251480 AF XY: 0.0139

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.0319

Gnomad ASJ exome AF: 0.00813

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.00833

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00955 AC: 13954 AN: 1461882 Hom.: 132 Cov.: 34 AF XY: 0.0103 AC XY: 7483 AN XY: 727236

African (AFR) AF: 0.00203 AC: 68 AN: 33480

American (AMR) AF: 0.0295 AC: 1319 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00715 AC: 187 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0293 AC: 2525 AN: 86258

European-Finnish (FIN) AF: 0.0125 AC: 669 AN: 53418

Middle Eastern (MID) AF: 0.0180 AC: 104 AN: 5768

European-Non Finnish (NFE) AF: 0.00771 AC: 8578 AN: 1112004

Other (OTH) AF: 0.00831 AC: 502 AN: 60394

GnomAD4 genome AF: 0.00891 AC: 1358 AN: 152330 Hom.: 16 Cov.: 33 AF XY: 0.00932 AC XY: 694 AN XY: 74496

African (AFR) AF: 0.00216 AC: 90 AN: 41574

American (AMR) AF: 0.0174 AC: 266 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0261 AC: 126 AN: 4830

European-Finnish (FIN) AF: 0.0149 AC: 158 AN: 10624

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00967 AC: 658 AN: 68028

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00823 Hom.: 8

Bravo AF: 0.00872

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.00774

EpiControl AF: 0.00741

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	2	Cardiomyopathy (2)
-	-	2	Hypertrophic cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Hypertrophic cardiomyopathy 1 (1)
-	-	1	Left ventricular noncompaction cardiomyopathy (1)
-	-	1	MYH7-related skeletal myopathy (1)
-	-	1	Myosin storage myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.5
DANN	Benign	0.62
PhyloP100		-0.42
Mutation Taster		=99/1	polymorphism (auto)

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: rs2754155; hg19: chr14-23886155;