11-47346294-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000256.3(MYBPC3):c.1003C>A(p.Arg335Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,138 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R335C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.37

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 6) in uniprot entity MYPC3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47346294-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1003C>A	p.Arg335Ser	missense_variant	12/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1003C>A	p.Arg335Ser	missense_variant	12/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1003C>A	p.Arg335Ser	missense_variant	11/34	5		A2
MYBPC3	ENST00000544791.1	c.1003C>A	p.Arg335Ser	missense_variant, NMD_transcript_variant	12/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247608 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134470

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461138 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726838

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
CardioboostCm	Benign	0.092
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Benign	0.27
Sift	Benign	0.069	T;T;T
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.91	P;.;.
Vest4		0.51
MutPred		0.56		Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);Loss of MoRF binding (P = 0.0464);
MVP		0.89
MPC		0.57
ClinPred		0.89	D
GERP RS		4.7
Varity_R		0.29
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs730880630; hg19: chr11-47367845;