rs775518991
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PM2PP3_ModeratePP5_Very_Strong
The NM_019892.6(INPP5E):βc.1760delβ(p.Val587GlyfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000412 in 1,551,940 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.000020 ( 0 hom., cov: 33)
Exomes π: 0.000044 ( 0 hom. )
Consequence
INPP5E
NM_019892.6 frameshift
NM_019892.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.26
Genes affected
INPP5E (HGNC:21474): (inositol polyphosphate-5-phosphatase E) The protein encoded by this gene is an inositol 1,4,5-trisphosphate (InsP3) 5-phosphatase. InsP3 5-phosphatases hydrolyze Ins(1,4,5)P3, which mobilizes intracellular calcium and acts as a second messenger mediating cell responses to various stimulation. Studies of the mouse counterpart suggest that this protein may hydrolyze phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,5-bisphosphate on the cytoplasmic Golgi membrane and thereby regulate Golgi-vesicular trafficking. Mutations in this gene cause Joubert syndrome; a clinically and genetically heterogenous group of disorders characterized by midbrain-hindbrain malformation and various associated ciliopathies that include retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 20 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP3
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Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 9-136430318-CA-C is Pathogenic according to our data. Variant chr9-136430318-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136430318-CA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
INPP5E | NM_019892.6 | c.1760del | p.Val587GlyfsTer7 | frameshift_variant | 9/10 | ENST00000371712.4 | |
INPP5E | NM_001318502.2 | c.1757del | p.Val586GlyfsTer7 | frameshift_variant | 9/10 | ||
INPP5E | XM_017014926.2 | c.1760del | p.Val587GlyfsTer7 | frameshift_variant | 9/10 | ||
INPP5E | XM_047423603.1 | c.1757del | p.Val586GlyfsTer7 | frameshift_variant | 9/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
INPP5E | ENST00000371712.4 | c.1760del | p.Val587GlyfsTer7 | frameshift_variant | 9/10 | 1 | NM_019892.6 | P1 | |
INPP5E | ENST00000676019.1 | c.1658del | p.Val553GlyfsTer7 | frameshift_variant | 9/10 | ||||
INPP5E | ENST00000674693.1 | downstream_gene_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152232Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000127 AC: 2AN: 157180Hom.: 0 AF XY: 0.0000121 AC XY: 1AN XY: 82684
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GnomAD4 exome AF: 0.0000436 AC: 61AN: 1399708Hom.: 0 Cov.: 34 AF XY: 0.0000406 AC XY: 28AN XY: 690396
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152232Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74366
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial aplasia of the vermis Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 20, 2022 | This sequence change creates a premature translational stop signal (p.Val587Glyfs*7) in the INPP5E gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 58 amino acid(s) of the INPP5E protein. This variant is present in population databases (rs775518991, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome 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: 217656). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the INPP5E protein in which other variant(s) (p.Pro597Leu) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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 | - - |
INPP5E-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 21, 2024 | The INPP5E c.1760delT variant is predicted to result in a frameshift and premature protein termination (p.Val587Glyfs*7). This variant has been reported in an individual with Joubert syndrome (Table S5, Bachmann-Gagescu et al. 2015. PubMed ID: 26092869) and it has also been reported in an individual with an inherited retinal degeneration (Figure 1, Sangermano et al. 2021. PubMed ID: 34188062). This variant is reported in 0.0033% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in INPP5E are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Rod-cone dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The INPP5E c.1760delT variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at