11-47350016-A-G

Position:

chr11-47350016-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2

The NM_000256.3(MYBPC3):c.503T>C(p.Val168Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000041 in 1,560,094 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000043 ( 2 hom. )

Consequence

MYBPC3
NM_000256.3 missense, splice_region

Scores

Splicing: ADA: 0.00007974

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 1.11

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a domain Ig-like C2-type 1 (size 103) in uniprot entity MYPC3_HUMAN there are 30 pathogenic changes around while only 10 benign (75%) in NM_000256.3

BP4

Computational evidence support a benign effect (MetaRNN=0.13914892).

BP6

Variant 11-47350016-A-G is Benign according to our data. Variant chr11-47350016-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179989.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.503T>C	p.Val168Ala	missense_variant, splice_region_variant	4/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.503T>C	p.Val168Ala	missense_variant, splice_region_variant	4/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.503T>C	p.Val168Ala	missense_variant, splice_region_variant	4/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.503T>C	p.Val168Ala	missense_variant, splice_region_variant, NMD_transcript_variant	4/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151484

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000625

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000710

AC:

AN:

168932

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

90134

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000513

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000433

AC:

AN:

1408486

Hom.:

Cov.:

AF XY:

0.0000604

AC XY:

AN XY:

695744

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000752

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151608

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74094

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000626

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000149

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000342

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 06, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 27, 2023	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 168 of the MYBPC3 protein (p.Val168Ala). This variant is present in population databases (rs727505267, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 179989). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 07, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 05, 2018	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 08, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with history of unexplained cardiac arrest (Mellor et al., 2017); This variant is associated with the following publications: (PMID: 28600387) -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Aug 22, 2014

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2019

The p.V168A variant (also known as c.503T>C), located in coding exon 4 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 503. The valine at codon 168 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in an unexplained cardiac arrest survivor; however, clinical details were limited (Mellor G et al. Circ Cardiovasc Genet, 2017 Jun;10:e001686). This amino acid position is not well conserved in available vertebrate species, and alanine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 24, 2014

Val168Ala in exon 4 of MYBPC3: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, 8 mammals (Chinese tree shrew, dolphin, killer whale, cat, dog, ferret, elep hant, manatee) have an alanine (Ala) at this position despite high nearby amino acid conservation. In addition, this variant was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign pr ediction is estimated to be correct 89% of the time (Jordan 2011). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

CardioboostCm

Benign

0.00040

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.38

CADD

Benign

9.0

DANN

Benign

0.88

DEOGEN2

Benign

0.20

T;T;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.75

T;T;T

M_CAP

Benign

0.064

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.79

N;.;.

MutationTaster

Benign

0.91

D;D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.078

Sift

Benign

0.27

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.13

MutPred

0.37

Loss of stability (P = 0.0539);Loss of stability (P = 0.0539);Loss of stability (P = 0.0539);

MVP

0.70

MPC

0.27

ClinPred

0.050

GERP RS

-2.0

Varity_R

0.070

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000080

dbscSNV1_RF

Benign

0.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over