rs397515916

Variant names:

• chr11-47342574-T-A
• rs397515916
• NM_000256.3:c.1624+4A>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PP3 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.1624+4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,584,178 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000208041: Published functional studies demonstrate that c.1624+4 A>T results in skipping of exon 17 (Helms et al., 2014" and additional evidence is available in ClinVar. The gene MYBPC3 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 splice_region, intron
• Scores: Splicing: ADA: 0.9685
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 2.40
• Publications: 9 publications found

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Specifications for MYBPC3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000208041: Published functional studies demonstrate that c.1624+4 A>T results in skipping of exon 17 (Helms et al., 2014; Singer et al., 2019); SCV000059070: This variant also been identified in 3/224880 chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is located in the 5' splice region multiple studies have demonstrated that it causes skipping of exon 17, leading to the introduction of a premature stop codon (Helms 2014, Ito 2017, Springer 2019).; SCV000219148: Studies have shown that this variant results in skipping of exon 17, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 25031304).; SCV004831425: Functional studies with peripheral blood, septal myectomy and transplant specimens have shown that this variant disrupts mRNA splicing, resulting in skipping of exon 17 and introduction of a premature translation stop codon (PMID: 25031304, 30645170).; SCV000917817: "This variant has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (Helms_2014). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16199542, 19574547, 22267749, 23782526, 25031304, 27688314)." Functional studies which show the variant to lead to exon 17 skipping and premature termination (Helms_2014).; SCV000320645: Skipping of exon 17, which is predicted to lead to a frameshift, was detected on analysis of cardiac tissue from an affected carrier, and RNA analysis in blood samples from carriers identified by another group also confirmed skipping of exon 17 (Helms AS et al. Circ Cardiovasc Genet. 2014;7(4):434-43; Singer ES et al. Circ Genom Precis Med. 2019;12(1):e002368).; SCV001344922: Functional RNA studies have shown that this variant causes skipping of exon 17, frameshift and premature truncation, resulting in a truncated or absent protein product (PMID: 25031304, 30645170).; SCV004801386: Functional studies have demonstrated that this variant results in skipping of exon 17 (Helms et al., 2014; Singer et al., 2019).; SCV005362869: Complementary DNA studies in myocardial samples showed that the c.1624+4A>T results in skipping of exon 17 (Helms et al. 2014. PubMed ID: 25031304; Singer et al. 2019. PubMed ID: 30645170).
• 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 11-47342574-T-A is Pathogenic according to our data. Variant chr11-47342574-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 42556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. 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
	MYBPC3	NM_000256.3	MANE Select	c.1624+4A>T		splice_region intron	N/A	NP_000247.2	Q14896-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.1624+4A>T		splice_region intron	N/A	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.1624+4A>T		splice_region intron	N/A	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.1624+4A>T		splice_region intron	N/A	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152102 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000133 AC: 3 AN: 224880 AF XY: 0.00

Gnomad AFR exome AF: 0.0000666

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: 0.0000197

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000384 AC: 55 AN: 1432076 Hom.: 0 Cov.: 31 AF XY: 0.0000296 AC XY: 21 AN XY: 708990

African (AFR) AF: 0.00 AC: 0 AN: 33092

American (AMR) AF: 0.00 AC: 0 AN: 42434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24226

East Asian (EAS) AF: 0.00 AC: 0 AN: 39346

South Asian (SAS) AF: 0.00 AC: 0 AN: 81516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5564

European-Non Finnish (NFE) AF: 0.0000484 AC: 53 AN: 1096168

Other (OTH) AF: 0.0000338 AC: 2 AN: 59140

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152102 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74308

African (AFR) AF: 0.0000241 AC: 1 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

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: 0.0000441 AC: 3 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (6)
4	-	-	Hypertrophic cardiomyopathy (4)
3	-	-	Hypertrophic cardiomyopathy 4 (3)
2	-	-	Cardiomyopathy (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Left ventricular noncompaction 10 (1)
1	-	-	MYBPC3-related disorder (1)
1	-	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.93
PhyloP100		2.4
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.79
Splicevardb		3.0
SpliceAI score (max)		0.16		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: rs397515916; hg19: chr11-47364125;