11-47335891-T-G

Variant names:

• chr11-47335891-T-G
• rs397515984
• NM_000256.3:c.2723A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y908C) has been classified as Uncertain significance.

• 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
• Publications: 2 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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

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.2723A>C	p.Tyr908Ser	missense	Exon 26 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.2723A>C	p.Tyr908Ser	missense	Exon 26 of 35	ENSP00000442795.1
	MYBPC3	ENST00000399249.6	TSL:5	c.2723A>C	p.Tyr908Ser	missense	Exon 25 of 34	ENSP00000382193.2
	MYBPC3	ENST00000544791.1	TSL:5	n.*228A>C		non_coding_transcript_exon	Exon 26 of 27	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

African (AFR) AF: 0.00 AC: 0 AN: 30360

American (AMR) AF: 0.0000297 AC: 1 AN: 33616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24538

East Asian (EAS) AF: 0.00 AC: 0 AN: 33922

South Asian (SAS) AF: 0.00 AC: 0 AN: 76752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5214

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067936

Other (OTH) AF: 0.00 AC: 0 AN: 56934

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0050	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
Mutation Taster		=38/62	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: rs397515984; hg19: chr11-47357442;