chr11-47351311-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_000256.3(MYBPC3):c.220G>A(p.Ala74Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,328 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A74A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.02

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 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000256.3

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.220G>A	p.Ala74Thr	missense_variant	Exon 2 of 35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 link	c.220G>A	p.Ala74Thr	missense_variant	Exon 2 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.220G>A	p.Ala74Thr	missense_variant	Exon 2 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.220G>A		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1428328

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32556

American (AMR)

AF:

0.00

AC:

AN:

40046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25500

East Asian (EAS)

AF:

0.00

AC:

AN:

37564

South Asian (SAS)

AF:

0.00

AC:

AN:

81876

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50970

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1094962

Other (OTH)

AF:

0.00

AC:

AN:

59134

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Uncertain:2

May 21, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on MYBPC3 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with a MYBPC3-related disease. This sequence change replaces alanine with threonine at codon 74 of the MYBPC3 protein (p.Ala74Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). -

Apr 27, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

CardioboostCm

Benign

0.00071

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;T;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.62

T;T;T

M_CAP

Benign

0.040

MetaRNN

Uncertain

0.49

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.89

L;.;.

PhyloP100

3.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.13

N;N;N

REVEL

Benign

0.050

Sift

Benign

0.087

T;T;T

Sift4G

Benign

0.076

T;T;T

Polyphen

0.32

B;.;.

Vest4

0.069

MutPred

0.28

Gain of glycosylation at A74 (P = 0.0475);Gain of glycosylation at A74 (P = 0.0475);Gain of glycosylation at A74 (P = 0.0475);

MVP

0.68

MPC

0.22

ClinPred

0.52

GERP RS

2.4

Varity_R

0.10

gMVP

0.17

Mutation Taster

=92/8

polymorphism

(source)

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

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chr11-47351311-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over