rs397515936
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000256.3(MYBPC3):c.1897+5G>A variant causes a splice donor 5th base, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
MYBPC3
NM_000256.3 splice_donor_5th_base, intron
NM_000256.3 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 4.51
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 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.1897+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1897+5G>A | splice_donor_5th_base_variant, intron_variant | 5 | NM_000256.3 | P4 | |||
MYBPC3 | ENST00000399249.6 | c.1897+5G>A | splice_donor_5th_base_variant, intron_variant | 5 | A2 | ||||
MYBPC3 | ENST00000544791.1 | c.1897+5G>A | splice_donor_5th_base_variant, intron_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1433978Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 710146
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1433978
Hom.:
Cov.:
36
AF XY:
AC XY:
0
AN XY:
710146
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 03, 2012 | Variant classified as Uncertain Significance - Favor Pathogenic. The 1897+5G>A v ariant has not been reported in the literature but has been identified in one in dividual with HCM out of >2,000 Caucasian individuals tested by our laboratory. The low frequency of the 1897+5G>A variant in this population supports a pathoge nic role. This variant is located in the 5' splice region but does not affect th e highly conserved +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. Computational splicing tools (SpliceSiteFinder-like, MaxEntSca n, NNSPLICE, GeneSplicer, Human Splicing Finder) predict that the variant may af fect splicing, though the accuracy of these tools has not been validated by our laboratory. Additional information is needed to fully access the clinical signif icance of the 1897+5G>A variant. - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 26, 2023 | ClinVar contains an entry for this variant (Variation ID: 42583). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28679633, 35508642). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 19 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. It affects a nucleotide within the consensus splice site. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 31, 2018 | The c.1897+5G>A intronic alteration consists of a G to A substitution nucleotides after coding exon 19 in the MYBPC3 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -11
Find out detailed SpliceAI scores and Pangolin per-transcript scores at