rs201098973

chr11-47349782-C-Achr11-47349782-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000256.3(MYBPC3):c.646G>T(p.Ala216Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,452,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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. A216T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.698

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 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 10 uncertain in NM_000256.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.12170273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.646G>T	p.Ala216Ser	missense_variant	5/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.646G>T	p.Ala216Ser	missense_variant	5/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.646G>T	p.Ala216Ser	missense_variant	5/34	5		A2
MYBPC3	ENST00000544791.1	c.646G>T	p.Ala216Ser	missense_variant, NMD_transcript_variant	5/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000416 AC: 1 AN: 240270 Hom.: 0 AF XY: 0.00000762 AC XY: 1 AN XY: 131246

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: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1452890 Hom.: 0 Cov.: 31 AF XY: 0.00000553 AC XY: 4 AN XY: 723034

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000466

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostCm	Benign	0.00032
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	12
Dann	Benign	0.42
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	0.93	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.60	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.49	T;T;T
Sift4G	Benign	0.75	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.22
MutPred		0.55		Gain of disorder (P = 0.0221);Gain of disorder (P = 0.0221);Gain of disorder (P = 0.0221);
MVP		0.67
MPC		0.20
ClinPred		0.017	T
GERP RS		-1.1
Varity_R		0.11
gMVP		0.61

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: rs201098973; hg19: chr11-47371333;