9-136434769-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_019892.6(INPP5E):c.907G>A(p.Val303Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,612,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V303L) has been classified as Uncertain significance.
Frequency
Consequence
NM_019892.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
INPP5E | NM_019892.6 | c.907G>A | p.Val303Met | missense_variant | 2/10 | ENST00000371712.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
INPP5E | ENST00000371712.4 | c.907G>A | p.Val303Met | missense_variant | 2/10 | 1 | NM_019892.6 | P1 | |
INPP5E | ENST00000676019.1 | c.907G>A | p.Val303Met | missense_variant | 2/10 | ||||
INPP5E | ENST00000675256.1 | c.97G>A | p.Val33Met | missense_variant | 1/2 | ||||
INPP5E | ENST00000674513.1 | n.178G>A | non_coding_transcript_exon_variant | 2/3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152068Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 246928Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134482
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1459890Hom.: 0 Cov.: 38 AF XY: 0.0000110 AC XY: 8AN XY: 726176
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74424
ClinVar
Submissions by phenotype
Familial aplasia of the vermis Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 303 of the INPP5E protein (p.Val303Met). This variant is present in population databases (rs746212325, gnomAD 0.003%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 23386033, 26092869). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217653). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt INPP5E protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 29, 2023 | Published functional studies demonstrate the variant results in reduced protein expression compared to wild type (Cilleros-Rodriguez et al., 2022); Not observed at a significant frequency in large population cohorts (gnomAD); 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, 23386033, 29987673, 26748598, 33270637, 36063381) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 14, 2022 | Variant summary: INPP5E c.907G>A (p.Val303Met) results in a conservative amino acid change located in the Inositol polyphosphate-related phosphatase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 246928 control chromosomes. c.907G>A has been reported in the literature in individuals affected with Joubert Syndrome And Related Disorders in the compound heterozygous state including in two affected siblings (Travaglini_2013, Bachmann-Gagescu_2015, Toma_2018). In each case, the variant was reported along with a different INPP5E variant (p.Arg585Cys and c.Gly341Ser) both of which are reported in HGMD in association with Joubert syndrome but have either not been reported in ClinVar (p.Arg585Cys) or are reported as conflicting interpretations in ClinVar (p.Gly341Ser). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One lab classified as pathogenic while two have classified as VUS. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at