chr11-47333572-C-T

Position:

• chr11-47333572-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000256.3(MYBPC3):​c.3175G>A​(p.Val1059Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.131

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10515785).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3175G>A	p.Val1059Met	missense_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.3175G>A	p.Val1059Met	missense_variant	29/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.3175G>A	p.Val1059Met	missense_variant	28/34	5		ENSP00000382193	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 08, 2018

This variant has not been reported in the literature in individuals with MYBPC3-related disease. 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. A computational algorithm designed to assess the pathogenicity of variants in MYBPC3 with regard to hypertrophic cardiomyopathy predicted this sequence change to be tolerated. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 1059 of the MYBPC3 protein (p.Val1059Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
CardioboostCm	Benign	0.0078
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.046	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.14	N;.;N
REVEL	Benign	0.036
Sift	Benign	0.17	T;.;T
Sift4G	Benign	0.11	T;T;T
Vest4		0.24
MVP		0.33
MPC		0.25
ClinPred		0.16	T
GERP RS		0.20
Varity_R		0.072
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs754747269; hg19: chr11-47355123;