rs121909375

chr11-47351356-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000256.3(MYBPC3):c.175A>G(p.Thr59Ala) 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 pathogenic outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. T59T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.159

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762
• PP5: Variant 11-47351356-T-C is Pathogenic according to our data. Variant chr11-47351356-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 8614.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.175A>G	p.Thr59Ala	missense_variant	2/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.175A>G	p.Thr59Ala	missense_variant	2/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.175A>G	p.Thr59Ala	missense_variant	2/34	5		A2
MYBPC3	ENST00000544791.1	c.175A>G	p.Thr59Ala	missense_variant, NMD_transcript_variant	2/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypertrophic cardiomyopathy 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 29, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
CardioboostCm	Benign	0.0040
BayesDel_addAF	Benign	0.0072	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	1.4
Dann	Benign	0.26
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.51	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.8	N;.;.
MutationTaster	Benign	3.3e-8	A;A;A
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.66	N;N;N
REVEL	Uncertain	0.33
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.65
MutPred		0.75		Gain of MoRF binding (P = 0.1191);Gain of MoRF binding (P = 0.1191);Gain of MoRF binding (P = 0.1191);
MVP		0.46
MPC		0.21
ClinPred		0.089	T
GERP RS		-2.4
Varity_R		0.23
gMVP		0.26

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: rs121909375; hg19: chr11-47372907;