rs368706722

Variant names:

• chr14-23414100-C-T
• rs368706722
• NM_000257.4:c.5562G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BP6_Very_Strong

The NM_000257.4(MYH7):​c.5562G>A​(p.Thr1854Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,612,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). The gene MYH7 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: MYH7 NM_000257.4 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:8
• Conservation: PhyloP100: -3.24
• Publications: 4 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]

MYH7 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1S

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• MYH7-related skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• myopathy, myosin storage, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myopathy, myosin storage, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital myopathy 7A, myosin storage, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ebstein anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyaline body myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Specifications for MYH7 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 14-23414100-C-T is Benign according to our data. Variant chr14-23414100-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.5562G>A	p.Thr1854Thr	splice_region synonymous	Exon 38 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.5562G>A	p.Thr1854Thr	splice_region synonymous	Exon 37 of 39	NP_001393933.1	P12883

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.5562G>A	p.Thr1854Thr	splice_region synonymous	Exon 38 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.5607G>A	p.Thr1869Thr	splice_region synonymous	Exon 38 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.5607G>A	p.Thr1869Thr	splice_region synonymous	Exon 38 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000116 AC: 29 AN: 249876 AF XY: 0.000141

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000175 AC: 256 AN: 1459934 Hom.: 0 Cov.: 33 AF XY: 0.000193 AC XY: 140 AN XY: 726376

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000220 AC: 245 AN: 1111956

Other (OTH) AF: 0.0000662 AC: 4 AN: 60388

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74458

African (AFR) AF: 0.0000241 AC: 1 AN: 41550

American (AMR) AF: 0.000196 AC: 3 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68020

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000240 Hom.: 0

Bravo AF: 0.000113

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	2	not specified (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	MYH7-related disorder (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Benign	0.78
PhyloP100		-3.2
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.65		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs368706722; hg19: chr14-23883309; COSMIC: COSV62517817; COSMIC: COSV62517817;