rs757222534
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_019892.6(INPP5E):c.1468G>T(p.Asp490Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,611,150 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. D490V) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
INPP5E | NM_019892.6 | c.1468G>T | p.Asp490Tyr | missense_variant | 7/10 | ENST00000371712.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
INPP5E | ENST00000371712.4 | c.1468G>T | p.Asp490Tyr | missense_variant | 7/10 | 1 | NM_019892.6 | P1 | |
INPP5E | ENST00000676019.1 | c.1366G>T | p.Asp456Tyr | missense_variant | 7/10 |
Frequencies
GnomAD3 genomes ? AF: 0.0000133 AC: 2AN: 150882Hom.: 0 Cov.: 30
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460268Hom.: 0 Cov.: 36 AF XY: 0.00000413 AC XY: 3AN XY: 726456
GnomAD4 genome ? AF: 0.0000133 AC: 2AN: 150882Hom.: 0 Cov.: 30 AF XY: 0.0000136 AC XY: 1AN XY: 73594
ClinVar
Submissions by phenotype
Familial aplasia of the vermis Pathogenic:1
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 | Mar 19, 2024 | Variant summary: INPP5E c.1468G>T (p.Asp490Tyr) results in a non-conservative amino acid change located in the Inositol polyphosphate-related phosphatase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246596 control chromosomes. c.1468G>T has been reported in the literature an in individuals affected with Joubert Syndrome with retinal involvement (Bachmann-Gagescu_2015, Phelps_2018). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function showing a strong reduction in protein levels without affecting ciliary targeting (Cilleros-Rodriguez_2022). ClinVar contains an entry for this variant (Variation ID: 217665). Based on the evidence outlined above, the variant was classified as a VUS. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at