chr11-47335891-T-G

Position:

• chr11-47335891-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000256.3(MYBPC3):​c.2723A>C​(p.Tyr908Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000726 in 1,377,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.94

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 domain Fibronectin type-III 2 (size 95) in uniprot entity MYPC3_HUMAN there are 23 pathogenic changes around while only 7 benign (77%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2723A>C	p.Tyr908Ser	missense_variant	26/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2723A>C	p.Tyr908Ser	missense_variant	26/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2723A>C	p.Tyr908Ser	missense_variant	25/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.*228A>C		non_coding_transcript_exon_variant	26/27	5		ENSP00000444259.1
MYBPC3	ENST00000544791.1	n.*228A>C		3_prime_UTR_variant	26/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1377856 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 678638

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000297

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Pathogenic	3.1	M;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.6	D;.;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0060	D;.;D
Sift4G	Uncertain	0.0050	D;D;D
Vest4		0.95
MVP		0.95
MPC		1.0
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.81
gMVP		0.83

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: rs397515984; hg19: chr11-47357442;