rs775518991

Positions:

• chr9-136430318-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PM2 PP3_Moderate PP5_Very_Strong

The NM_019892.6(INPP5E):​c.1760del​(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: INPP5E NM_019892.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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]

ACMG classification

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: Very rare variant in population databases, with high coverage
• PP3: 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: 3 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000127 AC: 2 AN: 157180 Hom.: 0 AF XY: 0.0000121 AC XY: 1 AN XY: 82684

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000328

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000436 AC: 61 AN: 1399708 Hom.: 0 Cov.: 34 AF XY: 0.0000406 AC XY: 28 AN XY: 690396

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000556

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

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

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs775518991; hg19: chr9-139324770;