rs863225201
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
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 Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
INPP5E | NM_019892.6 | c.1162G>T | p.Val388Leu | missense_variant, splice_region_variant | 5/10 | ENST00000371712.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
INPP5E | ENST00000371712.4 | c.1162G>T | p.Val388Leu | missense_variant, splice_region_variant | 5/10 | 1 | NM_019892.6 | P1 | |
INPP5E | ENST00000676019.1 | c.1060G>T | p.Val354Leu | missense_variant, splice_region_variant | 5/10 |
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
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 16, 2022 | 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. 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. 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). - |
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