11-47349911-T-G

Variant names:

• chr11-47349911-T-G
• rs727505168
• NM_000256.3:c.517A>C

Variant summary

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

The NM_000256.3(MYBPC3):​c.517A>C​(p.Thr173Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.78

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.

• PM1: In a domain Ig-like C2-type 1 (size 103) in uniprot entity MYPC3_HUMAN there are 30 pathogenic changes around while only 10 benign (75%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.517A>C	p.Thr173Pro	missense_variant	Exon 5 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.517A>C	p.Thr173Pro	missense_variant	Exon 5 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.517A>C	p.Thr173Pro	missense_variant	Exon 5 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.517A>C		non_coding_transcript_exon_variant	Exon 5 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
CardioboostCm	Uncertain	0.13
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;T;T
Eigen	Benign	0.10
Eigen_PC	Benign	0.057
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.024	D;D;D
Polyphen		0.44	B;.;.
Vest4		0.64
MVP		0.88
MPC		0.64
ClinPred		0.98	D
GERP RS		0.94
Varity_R		0.74
gMVP		0.77

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: rs727505168; hg19: chr11-47371462;