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rs121909374

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PVS1PM2_SupportingPP3_StrongPP5_Very_Strong

The NM_000256(MYBPC3):c.1624G>T(p.Glu542Ter) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

MYBPC3
NM_000256 stop_gained, splice_region

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 5.67

Links

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 21 ACMG points.

PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 33.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 11:47342578-C>A is Pathogenic according to our data. Variant chr11-47342578-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 430571. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYBPC3NM_000256.3 linkuse as main transcriptc.1624G>T p.Glu542Ter stop_gained, splice_region_variant 17/35 ENST00000545968.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYBPC3ENST00000545968.6 linkuse as main transcriptc.1624G>T p.Glu542Ter stop_gained, splice_region_variant 17/355 NM_000256.3 P2Q14896-1
MYBPC3ENST00000399249.6 linkuse as main transcriptc.1624G>T p.Glu542Ter stop_gained, splice_region_variant 16/345 A2
MYBPC3ENST00000544791.1 linkuse as main transcriptc.1624G>T p.Glu542Ter stop_gained, splice_region_variant, NMD_transcript_variant 17/275

Frequencies

GnomAD3 genomes
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 11, 2018The E542X variant in the MYBPC3 gene has been reported previously in a cohort of HCM patients, however, no specific clinical details were provided (Lopes et al., 2015). E542X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the MYBPC3 gene have been reported in Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Moreover, the E542X variant is not observed in large population cohorts (Lek et al., 2016). Finally, this variant was identified independently in a patient with HCM referred for genetic testing at GeneDx.In summary, E542X in the MYBPC3 gene is interpreted as a pathogenic variant. -
Hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJul 18, 2021This sequence change creates a premature translational stop signal (p.Glu542*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510). ClinVar contains an entry for this variant (Variation ID: 430571). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.65
Cadd
Pathogenic
44
Dann
Uncertain
1.0
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.98
D
MutationTaster
Benign
1.0
A;A;A
Vest4
0.95
GERP RS
4.6

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
DS_AG_spliceai
0.0
Position offset: 0
DS_AL_spliceai
0.0
Position offset: 34
DS_DG_spliceai
0.26
Position offset: 2
DS_DL_spliceai
0.010
Position offset: 0

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: rs121909374; hg19: chr11-47364129;