NM_000257.4:c.5655G>A

Variant names:

• chr14-23414007-C-T
• rs753392652
• NM_000257.4:c.5655G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3 PP3 PP5

The NM_000257.4(MYH7):​c.5655G>A​(p.Ala1885Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000513813: RNA studies demonstrate a damaging effect through in-frame skipping of exon 38 (PMID:27387980, 26782017, 30794915); SCV005888243: Multiple publications reports experimental evidence that this variant affects mRNA splicing, resulting in exon 38 skipping, confirmed by minigene assay and cDNA sequencing (e.g. Pajusalu_2016, Fiorillo_2016, Surikova_2019). PMID:32792077, 36264615, 27387980, 34135346, 34363016, 33333461, 26782017, 30794915, 33240318; SCV001754768: Experimental studies have shown that this variant affects proper mRNA splicing, resulting in an in-frame skipping of exon 38 and a shortening of the encoded protein by 32 amino acids (PMID:26782017, 27387980).; SCV002652975: RNA studies indicate that this variant disrupts normal splicing, leading to the in-frame skipping of exon 38 (Pajusalu S et al. Neuromuscul. Disord., 2016 Mar;26:236-9; Fiorillo C et al. Orphanet J Rare Dis, 2016 07;11:91).".

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: MYH7 NM_000257.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9964
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12 U:2
• Conservation: PhyloP100: -0.134
• Publications: 9 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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000513813: RNA studies demonstrate a damaging effect through in-frame skipping of exon 38 (PMID: 27387980, 26782017, 30794915); SCV005888243: Multiple publications reports experimental evidence that this variant affects mRNA splicing, resulting in exon 38 skipping, confirmed by minigene assay and cDNA sequencing (e.g. Pajusalu_2016, Fiorillo_2016, Surikova_2019). PMID: 32792077, 36264615, 27387980, 34135346, 34363016, 33333461, 26782017, 30794915, 33240318; SCV001754768: Experimental studies have shown that this variant affects proper mRNA splicing, resulting in an in-frame skipping of exon 38 and a shortening of the encoded protein by 32 amino acids (PMID: 26782017, 27387980).; SCV002652975: RNA studies indicate that this variant disrupts normal splicing, leading to the in-frame skipping of exon 38 (Pajusalu S et al. Neuromuscul. Disord., 2016 Mar;26:236-9; Fiorillo C et al. Orphanet J Rare Dis, 2016 07;11:91).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 14-23414007-C-T is Pathogenic according to our data. Variant chr14-23414007-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 378215.

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.5655G>A	p.Ala1885Ala	splice_region synonymous	Exon 38 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.5655G>A	p.Ala1885Ala	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.5655G>A	p.Ala1885Ala	splice_region synonymous	Exon 38 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.5700G>A	p.Ala1900Ala	splice_region synonymous	Exon 38 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.5700G>A	p.Ala1900Ala	splice_region synonymous	Exon 38 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251438 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1461826 Hom.: 0 Cov.: 33 AF XY: 0.0000440 AC XY: 32 AN XY: 727214

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1111996

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000534 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	2	-	Cardiomyopathy (4)
2	-	-	Hypertrophic cardiomyopathy 1 (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Dilated cardiomyopathy 1S (1)
1	-	-	Hypertrophic cardiomyopathy (1)
1	-	-	MYH7-related disorder (1)
1	-	-	MYH7-related skeletal myopathy (1)
1	-	-	Myopathy, myosin storage, autosomal recessive (1)
1	-	-	Myosin storage myopathy (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.83
PhyloP100		-0.13
Mutation Taster		=32/68	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
Splicevardb		3.0
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: rs753392652; hg19: chr14-23883216; COSMIC: COSV62518931; COSMIC: COSV62518931;