rs863225201
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_019892.6(INPP5E):c.1162G>T(p.Val388Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000174 in 1,611,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_019892.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
INPP5E | ENST00000371712.4 | c.1162G>T | p.Val388Leu | missense_variant, splice_region_variant | Exon 5 of 10 | 1 | NM_019892.6 | ENSP00000360777.3 | ||
INPP5E | ENST00000676019.1 | c.1060G>T | p.Val354Leu | missense_variant, splice_region_variant | Exon 5 of 10 | ENSP00000501984.1 |
Frequencies
GnomAD3 genomes AF: 0.0000133 AC: 2AN: 150760Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250054Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135604
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1460764Hom.: 0 Cov.: 53 AF XY: 0.0000193 AC XY: 14AN XY: 726692
GnomAD4 genome AF: 0.0000133 AC: 2AN: 150760Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 73640
ClinVar
Submissions by phenotype
Familial aplasia of the vermis Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 16, 2022 | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 388 of the INPP5E protein (p.Val388Leu). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with Joubert syndrome and related disorders and/or retinitis pigmentosa (PMID: 26092869; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 217663). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. - |
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 25, 2024 | Variant summary: INPP5E c.1162G>T (p.Val388Leu) results in a conservative amino acid change located in the inositol polyphosphate-related phosphatase domain (IPR000300) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250054 control chromosomes. c.1162G>T has been reported in the literature in the compound heterozygous state in at least one family where it segregated with disease in individuals affected with Joubert Syndrome (e.g. Bachmann-Gagescu_2015). These data indicate that the variant may be associated with disease. At least one in vitro study in HEK-293 cells shows that this variant results in reduced protein expression compared to wildtype (e.g. Cilleros-Rodriguez_2022). The following publications have been ascertained in the context of this evaluation (PMID: 26092869, 36063381). ClinVar contains an entry for this variant (Variation ID: 217663). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 30, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26092869) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at