11-47348451-A-T

Position:

• chr11-47348451-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_000256.3(MYBPC3):​c.745T>A​(p.Cys249Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.25

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.

• PM1: In a strand (size 10) in uniprot entity MYPC3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044248283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.745T>A	p.Cys249Ser	missense_variant	6/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.745T>A	p.Cys249Ser	missense_variant	6/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.745T>A	p.Cys249Ser	missense_variant	6/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.745T>A		non_coding_transcript_exon_variant	6/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
CardioboostCm	Benign	0.016
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.26
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.044	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.6	N;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	4.1	N;N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.12
MutPred		0.56		Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);
MVP		0.45
MPC		0.27
ClinPred		0.10	T
GERP RS		4.0
Varity_R		0.46
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397516071; hg19: chr11-47370002;