chr14-23417055-C-T

Variant names:

• chr14-23417055-C-T
• rs3729825
• NM_000257.4:c.4520-63G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000257.4(MYH7):​c.4520-63G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,613,984 control chromosomes in the GnomAD database, including 21,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3302 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18200 hom.)
• Consequence: MYH7 NM_000257.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.86
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-23417055-C-T is Benign according to our data. Variant chr14-23417055-C-T is described in ClinVar as Benign. ClinVar VariationId is 1264641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.4520-63G>A		intron_variant	Intron 32 of 39	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.4520-63G>A		intron_variant	Intron 31 of 38		NP_001393933.1
MHRT	NR_126491.1	n.651+47C>T		intron_variant	Intron 4 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.4520-63G>A		intron_variant	Intron 32 of 39	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.4520-63G>A		intron_variant	Intron 32 of 40			ENSP00000519070.1
MYH7	ENST00000713769.1	c.4520-63G>A		intron_variant	Intron 31 of 38			ENSP00000519071.1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28303 AN: 152070 Hom.: 3293 Cov.: 32

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0422

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.179

GnomAD4 exome AF: 0.149 AC: 218065 AN: 1461796 Hom.: 18200 Cov.: 36 AF XY: 0.146 AC XY: 105968 AN XY: 727194

African (AFR) AF: 0.322 AC: 10787 AN: 33480

American (AMR) AF: 0.0743 AC: 3323 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 4550 AN: 26136

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.0481 AC: 4145 AN: 86250

European-Finnish (FIN) AF: 0.111 AC: 5943 AN: 53386

Middle Eastern (MID) AF: 0.110 AC: 634 AN: 5768

European-Non Finnish (NFE) AF: 0.161 AC: 179565 AN: 1111960

Other (OTH) AF: 0.151 AC: 9104 AN: 60392

GnomAD4 genome AF: 0.186 AC: 28336 AN: 152188 Hom.: 3302 Cov.: 32 AF XY: 0.179 AC XY: 13341 AN XY: 74416

African (AFR) AF: 0.322 AC: 13379 AN: 41502

American (AMR) AF: 0.114 AC: 1745 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 600 AN: 3472

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5176

South Asian (SAS) AF: 0.0418 AC: 202 AN: 4828

European-Finnish (FIN) AF: 0.102 AC: 1082 AN: 10604

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10837 AN: 67994

Other (OTH) AF: 0.178 AC: 375 AN: 2112

Alfa AF: 0.174 Hom.: 1090

Bravo AF: 0.191

Asia WGS AF: 0.0410 AC: 145 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hypertrophic cardiomyopathy Benign:1

Sep 27, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.036
DANN	Benign	0.73
PhyloP100		-3.9
Mutation Taster		=100/0	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: rs3729825; hg19: chr14-23886264;