rs767039057

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000256.3(MYBPC3):​c.3294G>T​(p.Trp1098Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,443,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

1
4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.324
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.4187547).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYBPC3NM_000256.3 linkuse as main transcriptc.3294G>T p.Trp1098Cys missense_variant 30/35 ENST00000545968.6 NP_000247.2 Q14896-1A5YM48

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYBPC3ENST00000545968.6 linkuse as main transcriptc.3294G>T p.Trp1098Cys missense_variant 30/355 NM_000256.3 ENSP00000442795.1 Q14896-1
MYBPC3ENST00000399249.6 linkuse as main transcriptc.3294G>T p.Trp1098Cys missense_variant 29/345 ENSP00000382193.2 A8MXZ9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000346
AC:
5
AN:
1443530
Hom.:
0
Cov.:
34
AF XY:
0.00000419
AC XY:
3
AN XY:
716144
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000453
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000166
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 21, 2022In 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. This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 1098 of the MYBPC3 protein (p.Trp1098Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
CardioboostCm
Benign
0.0038
BayesDel_addAF
Benign
-0.091
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.077
T;T;T
Eigen
Benign
0.13
Eigen_PC
Benign
0.15
FATHMM_MKL
Benign
0.50
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.42
T;T;T
MetaSVM
Benign
-0.87
T
MutationAssessor
Benign
0.58
N;.;.
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-1.8
N;.;N
REVEL
Benign
0.21
Sift
Benign
0.039
D;.;D
Sift4G
Uncertain
0.024
D;D;D
Vest4
0.51
MVP
0.75
MPC
0.81
ClinPred
0.75
D
GERP RS
5.4
Varity_R
0.29
gMVP
0.66

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

LitVar

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

Other links and lift over

dbSNP: rs767039057; hg19: chr11-47354781; API