NM_002439.5:c.2319-1G>C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_002439.5(MSH3):c.2319-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_002439.5 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MSH3 | ENST00000265081.7 | c.2319-1G>C | splice_acceptor_variant, intron_variant | Intron 16 of 23 | 1 | NM_002439.5 | ENSP00000265081.6 | |||
MSH3 | ENST00000658259.1 | c.2151-1G>C | splice_acceptor_variant, intron_variant | Intron 16 of 23 | ENSP00000499617.1 | |||||
MSH3 | ENST00000667069.1 | c.2124-1G>C | splice_acceptor_variant, intron_variant | Intron 14 of 21 | ENSP00000499502.1 | |||||
MSH3 | ENST00000670357.1 | n.2319-1G>C | splice_acceptor_variant, intron_variant | Intron 16 of 24 | ENSP00000499791.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 27
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 4 Pathogenic:1
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -
not provided Pathogenic:1
This sequence change affects an acceptor splice site in intron 16 of the MSH3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH3 are known to be pathogenic (PMID: 27476653). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with MSH3-associated polyposis (PMID: 27476653; Invitae). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at