rs397516081
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000256.3(MYBPC3):c.926+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,431,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000256.3 splice_region, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.926+4A>G | splice_region_variant, intron_variant | ENST00000545968.6 | NP_000247.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.926+4A>G | splice_region_variant, intron_variant | 5 | NM_000256.3 | ENSP00000442795.1 | ||||
MYBPC3 | ENST00000399249.6 | c.926+4A>G | splice_region_variant, intron_variant | 5 | ENSP00000382193.2 | |||||
MYBPC3 | ENST00000544791.1 | n.926+4A>G | splice_region_variant, intron_variant | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000140 AC: 2AN: 1431830Hom.: 0 Cov.: 38 AF XY: 0.00000141 AC XY: 1AN XY: 709186
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 10, 2020 | The c.926+4A>G variant in MYBPC3 has been reported in one individual with dilated cardiomyopathy (DCM; Ito 2017 PMID: 28679633) and was absent from large population studies. This variant is located in the 5' splice region. Computational tools predict a splicing impact and functional studies using a cell-based minigene splicing assay provide some evidence that this variant impacts splicing (Ito 2017 PMID: 28679633). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS3_Supporting. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 02, 2020 | Reported in association with cardiomyopathy (Ito et al., 2017); however, additional clinical information was not provided; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28679633) - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 12, 2021 | This sequence change falls in intron 11 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 of the intron. This variant is present in population databases (rs397516081, ExAC 0.009%). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 28679633). ClinVar contains an entry for this variant (Variation ID: 42803). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 28679633). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at