rs121909375

Positions:

• 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).

• 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	Protein	UniProt
MYBPC3	NM_000256.3	c.175A>G	p.Thr59Ala	missense_variant	2/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.175A>G	p.Thr59Ala	missense_variant	2/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.175A>G	p.Thr59Ala	missense_variant	2/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.175A>G	p.Thr59Ala	missense_variant, NMD_transcript_variant	2/27	5		ENSP00000444259

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;