rs752300607

Positions:

chr9-136430325-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_019892.6(INPP5E):c.1754G>A(p.Arg585His) variant causes a missense change. The variant allele was found at a frequency of 0.0000522 in 1,552,150 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R585C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

INPP5E
NM_019892.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.99

Variant links:

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]

INPP5E links:

INPP5E (HGNC:):

INPP5E links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 9-136430325-C-T is Pathogenic according to our data. Variant chr9-136430325-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136430325-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INPP5E	NM_019892.6 linkuse as main transcript	c.1754G>A	p.Arg585His	missense_variant	9/10	ENST00000371712.4	NP_063945.2	Q9NRR6-1
INPP5E	NM_001318502.2 linkuse as main transcript	c.1751G>A	p.Arg584His	missense_variant	9/10		NP_001305431.1	Q9NRR6
INPP5E	XM_017014926.2 linkuse as main transcript	c.1754G>A	p.Arg585His	missense_variant	9/10		XP_016870415.1
INPP5E	XM_047423603.1 linkuse as main transcript	c.1751G>A	p.Arg584His	missense_variant	9/10		XP_047279559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
INPP5E	ENST00000371712.4 linkuse as main transcript	c.1754G>A	p.Arg585His	missense_variant	9/10	1	NM_019892.6	ENSP00000360777.3	Q9NRR6-1
INPP5E	ENST00000676019.1 linkuse as main transcript	c.1652G>A	p.Arg551His	missense_variant	9/10			ENSP00000501984.1	Q9NRR6-2
INPP5E	ENST00000674693.1 linkuse as main transcript	n.*10G>A		downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000572

AC:

AN:

157454

Hom.:

AF XY:

0.0000483

AC XY:

AN XY:

82838

show subpopulations

Gnomad AFR exome

AF:

0.000113

Gnomad AMR exome

AF:

0.000121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000867

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000491

Gnomad OTH exome

AF:

0.000225

GnomAD4 exome

AF:

0.0000529

AC:

AN:

1399930

Hom.:

Cov.:

AF XY:

0.0000434

AC XY:

AN XY:

690530

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.0000840

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:

0.0000621

Gnomad4 OTH exome

AF:

0.0000517

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.000121

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000494

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000103

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial aplasia of the vermis

Pathogenic:2

Pathogenic, criteria provided, single submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Feb 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 585 of the INPP5E protein (p.Arg585His). This variant is present in population databases (rs752300607, gnomAD 0.02%). This missense change has been observed in individual(s) with Joubert syndrome and/or rod cone degeneration (PMID: 26092869, 34188062). 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: 217657). 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%. This variant disrupts the p.Arg585 amino acid residue in INPP5E. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23386033, 28559085). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

INPP5E-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2023

The INPP5E c.1754G>A variant is predicted to result in the amino acid substitution p.Arg585His. This variant along with a second variant in this gene was reported in an individual with Joubert syndrome (Table S5, Bachmann-Gagescu et al 2015. PubMed ID: 26092869) and found in two families with mild retinal degenerations (Table 1 and Figure 1, Sangermano et al 2021. PubMed ID: 34188062). This variant was reported as pathogenic in a carrier screening study (Table S1, Capalbo A et al 2019. PubMed ID: 31589614). This variant is reported in 0.023% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-139324777-C-T). In ClinVar, this variant is interpreted as uncertain/likly pathogenic/pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/217657/?new_evidence=false). A different variant affecting the same amino acid p.Arg585Cys has been reported in the compound heterozygous state in several affected individuals from two unrelated families with Joubert syndrome (Table1, Travaglini. 2013. PubMed ID: 23386033;Toma. 2018. PubMed ID: 29987673). Take together, this variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 19, 2024

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 31589614, 23386033, 33057194, 31964843, 29987673, 35982159, 26092869, 34188062, 28559085, 38113761, 38219857) -

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.1754G>A 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: PM2, PP3, PM1, PM3. Based on this evidence we have classified this variant as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.97

MutPred

0.82

Loss of MoRF binding (P = 0.0094);

MVP

0.99

MPC

1.2

ClinPred

0.93

GERP RS

5.5

Varity_R

0.83

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over