rs121918130

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_019892.6(INPP5E):c.1132C>T(p.Arg378Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,304,334 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 (★★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

INPP5E
NM_019892.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.08

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 9-136433182-G-A is Pathogenic according to our data. Variant chr9-136433182-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INPP5E	NM_019892.6 linkuse as main transcript	c.1132C>T	p.Arg378Cys	missense_variant	4/10	ENST00000371712.4	NP_063945.2	Q9NRR6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712.4 linkuse as main transcript	c.1132C>T	p.Arg378Cys	missense_variant	4/10	1	NM_019892.6	ENSP00000360777.3		Q9NRR6-1
INPP5E	ENST00000676019.1 linkuse as main transcript	c.1035-5C>T		splice_region_variant, intron_variant				ENSP00000501984.1		Q9NRR6-2

Frequencies

GnomAD3 genomes

AF:

0.0000400

AC:

AN:

125126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000654

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000236

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000167

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000338

AC:

AN:

236434

Hom.:

AF XY:

0.0000154

AC XY:

AN XY:

129510

show subpopulations

Gnomad AFR exome

AF:

0.000205

Gnomad AMR exome

AF:

0.0000299

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:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000170

AC:

AN:

1179208

Hom.:

Cov.:

AF XY:

0.0000169

AC XY:

AN XY:

590820

show subpopulations

Gnomad4 AFR exome

AF:

0.0000820

Gnomad4 AMR exome

AF:

0.0000263

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000270

Gnomad4 SAS exome

AF:

0.0000123

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000613

GnomAD4 genome

AF:

0.0000400

AC:

AN:

125126

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

60422

show subpopulations

Gnomad4 AFR

AF:

0.0000654

Gnomad4 AMR

AF:

0.0000851

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000236

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000167

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000457

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000683

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Clubfoot;C0013274:Patent ductus arteriosus;C0025990:Micrognathia;C0033785:Pseudoarthrosis;C0265677:Hemivertebrae;C0345375:Short femur;C0345394:Vertebral hypoplasia;C0410528:Skeletal dysplasia;C0432163:Vertebral segmentation defect;C0746102:Chronic lung disease;C1145670:Respiratory failure;C2112942:Preaxial foot polydactyly;C2981150:Cleft palate;C4021862:Absent epiphyses;C4025010:Coat hanger sign of ribs;C5441745:Abnormal pulmonary interstitial morphology

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

- -

INPP5E-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2024

The INPP5E c.1132C>T variant is predicted to result in the amino acid substitution p.Arg378Cys. This variant has been reported in the homozygous state in two related individuals with Joubert Syndrome; an in vitro enzymatic assay in this same study showed the p.Arg378Cys variant has impaired 5-phosphatase activity compared to wildtype (Bielas et al 2009. PubMed ID: 19668216). This variant has also been reported in an additional individual with retinal disease (Table S1, Karali et al. 2022. PubMed ID: 36460718). This variant is reported in 0.021% of alleles in individuals of African descent in gnomAD. A different substitution of this amino acid (p.Arg378His) has also been reported in the compound heterozygous state in an individual with Leber congenital amaurosis (Porto et al. 2017. PubMed ID: 29186038). Given the evidence, we interpret c.1132C>T (p.Arg378Cys) as likely pathogenic. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2018

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 22, 2024

Published functional studies demonstrate a damaging effect: inability to block Akt phosphorylation in the presence of PDGF stimulation (PMID: 19668216); 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: 19668216, 23022135, 27401686, 23386033, 15786477, 30755392) -

Joubert syndrome 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2009

- -

Joubert syndrome and related disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 31, 2022

Variant summary: INPP5E c.1132C>T (p.Arg378Cys) results in a non-conservative amino acid change located in the Inositol polyphosphate-related phosphatase domain (IPR000300) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.4e-05 in 236434 control chromosomes. c.1132C>T has been reported in the literature in multiple individuals affected with Joubert Syndrome And Related Disorders (example, Bielas_2009, Sangermano_2021, Sheck_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Bielas_2009). The most pronounced variant effect results in approximately 50% of normal 5'-phosphatase activity towards PtdIns(4,5)P2 as substrate corroborated by a zebrafish model (Xu_2017). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial aplasia of the vermis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 15, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg378 amino acid residue in INPP5E. Other variant(s) that disrupt this residue have been observed in individuals with INPP5E-related conditions (PMID: 29186038), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects INPP5E function (PMID: 19668216). 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. ClinVar contains an entry for this variant (Variation ID: 400). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 15786477, 19668216). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121918130, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 378 of the INPP5E protein (p.Arg378Cys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.80

MutationAssessor

Pathogenic

4.2

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.4

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MVP

0.97

MPC

1.2

ClinPred

1.0

GERP RS

3.0

Varity_R

0.92

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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