rs397515936

Variant names:

• chr11-47341133-C-T
• rs397515936
• NM_000256.3:c.1897+5G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000256.3(MYBPC3):​c.1897+5G>A variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.51
• Publications: 1 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD 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
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1897+5G>A		splice_region_variant, intron_variant	Intron 19 of 34	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1897+5G>A		splice_region_variant, intron_variant	Intron 19 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1897+5G>A		splice_region_variant, intron_variant	Intron 18 of 33	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1897+5G>A		splice_region_variant, intron_variant	Intron 19 of 26	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1433978 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 710146

African (AFR) AF: 0.00 AC: 0 AN: 32874

American (AMR) AF: 0.00 AC: 0 AN: 41252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25630

East Asian (EAS) AF: 0.00 AC: 0 AN: 38256

South Asian (SAS) AF: 0.00 AC: 0 AN: 82538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096578

Other (OTH) AF: 0.00 AC: 0 AN: 59272

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The 1897+5G>A v ariant has not been reported in the literature but has been identified in one in dividual with HCM out of >2,000 Caucasian individuals tested by our laboratory. The low frequency of the 1897+5G>A variant in this population supports a pathoge nic role. This variant is located in the 5' splice region but does not affect th e highly conserved +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. Computational splicing tools (SpliceSiteFinder-like, MaxEntSca n, NNSPLICE, GeneSplicer, Human Splicing Finder) predict that the variant may af fect splicing, though the accuracy of these tools has not been validated by our laboratory. Additional information is needed to fully access the clinical signif icance of the 1897+5G>A variant. -

Hypertrophic cardiomyopathy Uncertain:1

May 26, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 42583). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28679633, 35508642). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 19 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. It affects a nucleotide within the consensus splice site. -

Cardiovascular phenotype Uncertain:1

May 31, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1897+5G>A intronic alteration consists of a G to A substitution nucleotides after coding exon 19 in the MYBPC3 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	36
DANN	Benign	0.94
PhyloP100		4.5
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.77		Position offset: -11

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

Other links and lift over

dbSNP: rs397515936; hg19: chr11-47362684;