NM_000257.4:c.5284-45G>T

Variant names:

• chr14-23415315-C-A
• rs45468101
• NM_000257.4:c.5284-45G>T

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.5284-45G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,614,246 control chromosomes in the GnomAD database, including 409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (43 hom., cov: 32)
  • Exomes 𝑓: 0.012 (366 hom.)
• Consequence: MYH7 NM_000257.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.20
• Publications: 2 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]

ENSG00000258444 (HGNC:):

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=-0.96).
• BP6: Variant 14-23415315-C-A is Benign according to our data. Variant chr14-23415315-C-A is described in ClinVar as Benign. ClinVar VariationId is 188643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0698 is higher than 0.05.

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.5284-45G>T		intron	N/A	NP_000248.2
	MYH7	NM_001407004.1		c.5284-45G>T		intron	N/A	NP_001393933.1
	MHRT	NR_126491.1		n.-135C>A		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.5284-45G>T		intron	N/A	ENSP00000347507.3
	MYH7	ENST00000713768.1		c.5284-45G>T		intron	N/A	ENSP00000519070.1
	MYH7	ENST00000713769.1		c.5284-45G>T		intron	N/A	ENSP00000519071.1

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2236 AN: 152236 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.00984

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.0758

Gnomad SAS AF: 0.0360

Gnomad FIN AF: 0.00677

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.00894

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0218 AC: 5492 AN: 251484 AF XY: 0.0217

Gnomad AFR exome AF: 0.00910

Gnomad AMR exome AF: 0.0360

Gnomad ASJ exome AF: 0.0305

Gnomad EAS exome AF: 0.0759

Gnomad FIN exome AF: 0.00707

Gnomad NFE exome AF: 0.00948

Gnomad OTH exome AF: 0.0262

GnomAD4 exome AF: 0.0125 AC: 18271 AN: 1461892 Hom.: 366 Cov.: 34 AF XY: 0.0132 AC XY: 9601 AN XY: 727246

African (AFR) AF: 0.00995 AC: 333 AN: 33480

American (AMR) AF: 0.0347 AC: 1551 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0335 AC: 875 AN: 26136

East Asian (EAS) AF: 0.0819 AC: 3251 AN: 39700

South Asian (SAS) AF: 0.0315 AC: 2718 AN: 86258

European-Finnish (FIN) AF: 0.00659 AC: 352 AN: 53418

Middle Eastern (MID) AF: 0.0598 AC: 345 AN: 5768

European-Non Finnish (NFE) AF: 0.00698 AC: 7757 AN: 1112012

Other (OTH) AF: 0.0180 AC: 1089 AN: 60396

GnomAD4 genome AF: 0.0148 AC: 2256 AN: 152354 Hom.: 43 Cov.: 32 AF XY: 0.0158 AC XY: 1177 AN XY: 74504

African (AFR) AF: 0.00993 AC: 413 AN: 41588

American (AMR) AF: 0.0241 AC: 369 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 126 AN: 3472

East Asian (EAS) AF: 0.0760 AC: 393 AN: 5170

South Asian (SAS) AF: 0.0360 AC: 174 AN: 4828

European-Finnish (FIN) AF: 0.00677 AC: 72 AN: 10628

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.00894 AC: 608 AN: 68038

Other (OTH) AF: 0.0383 AC: 81 AN: 2116

Alfa AF: 0.0107 Hom.: 6

Bravo AF: 0.0170

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.34
DANN	Benign	0.53
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs45468101; hg19: chr14-23884524; COSMIC: COSV62517500; COSMIC: COSV62517500;