Genetic Variant MYBPC3:p.Thr885Arg (chr11-47335960-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000256.3(MYBPC3):c.2654C>G(p.Thr885Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000708 in 1,412,348 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. T885M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.44

Publications

0 publications found

Variant links:

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

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.2654C>G	p.Thr885Arg	missense_variant	Exon 26 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYBPC3	ENST00000545968.6 link	c.2654C>G	p.Thr885Arg	missense_variant	Exon 26 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6 link	c.2654C>G	p.Thr885Arg	missense_variant	Exon 25 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1 link	n.*159C>G		non_coding_transcript_exon_variant	Exon 26 of 27	5		ENSP00000444259.1
MYBPC3	ENST00000544791.1 link	n.*159C>G		3_prime_UTR_variant	Exon 26 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.08e-7

AC:

AN:

1412348

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

699122

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31506

American (AMR)

AF:

0.00

AC:

AN:

38168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24252

East Asian (EAS)

AF:

0.00

AC:

AN:

37134

South Asian (SAS)

AF:

0.00

AC:

AN:

78558

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4282

European-Non Finnish (NFE)

AF:

9.19e-7

AC:

AN:

1088598

Other (OTH)

AF:

0.00

AC:

AN:

58272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

CardioboostCm

Benign

0.035

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;T;T

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.97

D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Uncertain

-0.13

MutationAssessor

Pathogenic

3.0

M;.;.

PhyloP100

6.4

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.4

D;.;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Vest4

0.76

MVP

0.90

MPC

0.87

ClinPred

0.99

GERP RS

5.3

Varity_R

0.80

gMVP

0.81

Mutation Taster

=29/71

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over