11-47349899-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000256.3(MYBPC3):c.529C>A(p.Arg177Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,455,278 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. R177C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.75

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47349899-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.529C>A	p.Arg177Ser	missense_variant	5/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.529C>A	p.Arg177Ser	missense_variant	5/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.529C>A	p.Arg177Ser	missense_variant	5/34	5		A2
MYBPC3	ENST00000544791.1	c.529C>A	p.Arg177Ser	missense_variant, NMD_transcript_variant	5/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000856 AC: 2 AN: 233730 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 127454

Gnomad AFR exome AF: 0.0000742

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: 0.00000949

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1455278 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723300

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
CardioboostCm	Benign	0.028
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T;T
Eigen	Benign	-0.022
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.036	D;D;D
Sift4G	Benign	0.078	T;T;T
Polyphen		0.046	B;.;.
Vest4		0.52
MutPred		0.70		Loss of methylation at R177 (P = 0.0332);Loss of methylation at R177 (P = 0.0332);Loss of methylation at R177 (P = 0.0332);
MVP		0.87
MPC		0.50
ClinPred		0.64	D
GERP RS		4.8
Varity_R		0.42
gMVP		0.73

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: rs193922385; hg19: chr11-47371450;