dbSNP rs730880569: MYBPC3:p.Ala848Val (chr11-47337450-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_000256.3(MYBPC3):c.2543C>T(p.Ala848Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 9.60

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 Uncertain_significance. Variant got 4 ACMG points.

PM1

In a domain Fibronectin type-III 1 (size 96) in uniprot entity MYPC3_HUMAN there are 31 pathogenic changes around while only 3 benign (91%) in NM_000256.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.2543C>T	p.Ala848Val	missense_variant	Exon 25 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.2543C>T	p.Ala848Val	missense_variant	Exon 25 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.2543C>T	p.Ala848Val	missense_variant	Exon 24 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.*48C>T		non_coding_transcript_exon_variant	Exon 25 of 27	5		ENSP00000444259.1	F5GZR4
MYBPC3	ENST00000544791.1 link	n.*48C>T		3_prime_UTR_variant	Exon 25 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000808

AC:

AN:

247484

Hom.:

AF XY:

0.00000745

AC XY:

AN XY:

134280

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460764

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726660

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Uncertain:1

Aug 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Oct 13, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy

Uncertain:1

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 848 of the MYBPC3 protein (p.Ala848Val). This variant is present in population databases (rs730880569, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 23816408). ClinVar contains an entry for this variant (Variation ID: 1677564). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Ala848 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 23816408, 25740977, 33782553), which suggests that this may be a clinically significant amino acid residue. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

CardioboostCm

Uncertain

0.10

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

T;T;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Uncertain

0.62

MutationAssessor

Pathogenic

4.4

H;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.6

D;.;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.0020

D;D;D

Vest4

0.88

MVP

0.92

MPC

0.83

ClinPred

0.99

GERP RS

4.6

Varity_R

0.88

gMVP

0.90

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

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