11-47350582-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000256.3(MYBPC3):c.326C>A(p.Ala109Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign 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. A109T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.522

Publications

1 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09741905).

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.326C>A	p.Ala109Asp	missense	Exon 3 of 35	NP_000247.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.326C>A	p.Ala109Asp	missense	Exon 3 of 35	ENSP00000442795.1
MYBPC3	ENST00000399249.6	TSL:5	c.326C>A	p.Ala109Asp	missense	Exon 3 of 34	ENSP00000382193.2
MYBPC3	ENST00000544791.1	TSL:5	n.326C>A		non_coding_transcript_exon	Exon 3 of 27	ENSP00000444259.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1372004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

678408

African (AFR)

AF:

0.00

AC:

AN:

28864

American (AMR)

AF:

0.00

AC:

AN:

22970

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23148

East Asian (EAS)

AF:

0.00

AC:

AN:

35854

South Asian (SAS)

AF:

0.00

AC:

AN:

73786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49120

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5096

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1076530

Other (OTH)

AF:

0.00

AC:

AN:

56636

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Uncertain:1

Nov 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MYBPC3-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with aspartic acid at codon 109 of the MYBPC3 protein (p.Ala109Asp). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and aspartic acid.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

CardioboostCm

Benign

0.0017

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.13

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.55

M_CAP

Benign

0.062

MetaRNN

Benign

0.097

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

0.52

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.64

REVEL

Benign

0.034

Sift

Benign

0.20

Sift4G

Benign

0.37

Polyphen

0.23

Vest4

0.13

MutPred

0.28

Gain of solvent accessibility (P = 0.0109)

MVP

0.76

MPC

0.33

ClinPred

0.13

GERP RS

1.0

Varity_R

0.16

gMVP

0.48

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over