rs1398838997
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002225.5(IVD):c.287-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. 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_002225.5 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
IVD | NM_002225.5 | c.287-1G>A | splice_acceptor_variant, intron_variant | ENST00000487418.8 | NP_002216.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IVD | ENST00000487418.8 | c.287-1G>A | splice_acceptor_variant, intron_variant | 1 | NM_002225.5 | ENSP00000418397.3 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152230Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461850Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727230
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74366
ClinVar
Submissions by phenotype
Isovaleryl-CoA dehydrogenase deficiency Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 27, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 17, 2023 | This sequence change affects an acceptor splice site in intron 3 of the IVD 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 IVD are known to be pathogenic (PMID: 16602101). This variant is present in population databases (no rsID available, gnomAD 0.05%). Disruption of this splice site has been observed in individuals with isovaleric acidemia (Invitae). ClinVar contains an entry for this variant (Variation ID: 552580). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 15, 2017 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at