rs727505191

Positions:

• chr11-47333557-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000256.3(MYBPC3):​c.3190G>A​(p.Asp1064Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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)
• Consequence: MYBPC3 NM_000256.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.74

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius 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/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3190G>A	p.Asp1064Asn	missense_variant, splice_region_variant	29/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3190G>A	p.Asp1064Asn	missense_variant, splice_region_variant	29/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.3190G>A	p.Asp1064Asn	missense_variant, splice_region_variant	28/34	5		ENSP00000382193	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 15, 2014

The Asp1064Asn variant in MYBPC3 has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction to ols and conservation analysis do not provide strong evidence for or against an i mpact the protein. However, this variant is located in the last base of the exon , which is part of the 5? splice region and computational tools predict that thi s variant may alter splicing. However, these computational tools are not predict ive enough to determine pathogenicity. Other pathogenic splice variants have bee n reported in this region (3190+1G>A, 3190+2T>G, and 3190+5G>A). In summary, the clinical significance of the Asp1064Asn variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
CardioboostCm	Benign	0.073
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;T;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.0	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.9	D;.;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Vest4		0.69
MVP		0.96
MPC		0.52
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.61
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.56		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs727505191; hg19: chr11-47355108;