14-23416924-G-T

Variant names:

• chr14-23416924-G-T
• rs397516225
• NM_000257.4:c.4588C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_000257.4(MYH7):​c.4588C>A​(p.Arg1530Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1530R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH7 NM_000257.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.889
• 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: Benign. The variant received -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 14-23416924-G-T is Benign according to our data. Variant chr14-23416924-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1741681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.889 with no splicing effect.

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.4588C>A	p.Arg1530Arg	synonymous	Exon 33 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.4588C>A	p.Arg1530Arg	synonymous	Exon 32 of 39	NP_001393933.1	P12883
	MHRT	NR_126491.1		n.567G>T		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.4588C>A	p.Arg1530Arg	synonymous	Exon 33 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.4588C>A	p.Arg1530Arg	synonymous	Exon 33 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.4588C>A	p.Arg1530Arg	synonymous	Exon 33 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.79
PhyloP100		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs397516225; hg19: chr14-23886133;