chr11-47333953-C-A

Variant names:

• chr11-47333953-C-A
• rs727504942
• NM_000256.3:c.2963G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000256.3(MYBPC3):​c.2963G>T​(p.Gly988Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000203 in 1,430,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G988R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 7.56
• Publications: 0 publications found

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]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.2963G>T	p.Gly988Val	missense	Exon 28 of 35	NP_000247.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.2963G>T	p.Gly988Val	missense	Exon 28 of 35	ENSP00000442795.1
	MYBPC3	ENST00000399249.6	TSL:5	c.2963G>T	p.Gly988Val	missense	Exon 27 of 34	ENSP00000382193.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000203 AC: 29 AN: 1430692 Hom.: 0 Cov.: 33 AF XY: 0.0000169 AC XY: 12 AN XY: 708852

African (AFR) AF: 0.0000305 AC: 1 AN: 32770

American (AMR) AF: 0.00 AC: 0 AN: 40014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25558

East Asian (EAS) AF: 0.0000263 AC: 1 AN: 37996

South Asian (SAS) AF: 0.00 AC: 0 AN: 81600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.0000237 AC: 26 AN: 1096754

Other (OTH) AF: 0.0000169 AC: 1 AN: 59250

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000469 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Cardiomyopathy (2)
-	2	-	Hypertrophic cardiomyopathy (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostCm	Uncertain	0.27
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.6
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-8.1	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.78
MVP		0.96
MPC		0.93
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.97
gMVP		0.86
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs727504942; hg19: chr11-47355504;