9-136433182-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R378H) has been classified 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:8

Conservation

PhyloP100: 4.08

Publications

15 publications found

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 Gene-Disease associations (from GenCC):

Joubert syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
MORM syndrome
Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, ClinGen, Orphanet
COACH syndrome 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome with ocular defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

INPP5E links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_019892.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-136433181-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 866268.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 0.50742 (below the threshold of 3.09). Trascript score misZ: -1.9401 (below the threshold of 3.09). GenCC associations: The gene is linked to Joubert syndrome with ocular defect, MORM syndrome, Joubert syndrome 1, Joubert syndrome, COACH syndrome 1.

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 CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136433182-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136433182-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136433182-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136433182-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136433182-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136433182-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136433182-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136433182-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136433182-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136433182-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136433182-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136433182-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136433182-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136433182-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136433182-G-A is described in CliVar as Pathogenic/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 rank	MANE	Protein	UniProt
INPP5E	NM_019892.6 link	c.1132C>T	p.Arg378Cys	missense_variant	Exon 4 of 10	ENST00000371712.4	NP_063945.2	Q9NRR6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712.4 link	c.1132C>T	p.Arg378Cys	missense_variant	Exon 4 of 10	1	NM_019892.6	ENSP00000360777.3		Q9NRR6-1
INPP5E	ENST00000676019.1 link	c.1035-5C>T		splice_region_variant, intron_variant	Intron 3 of 9			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

GnomAD2 exomes

AF:

0.0000338

AC:

AN:

236434

AF XY:

0.0000154

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 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

African (AFR)

AF:

0.0000820

AC:

AN:

24386

American (AMR)

AF:

0.0000263

AC:

AN:

38044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21880

East Asian (EAS)

AF:

0.0000270

AC:

AN:

37034

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81378

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5192

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

887316

Other (OTH)

AF:

0.0000613

AC:

AN:

48912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000400

AC:

AN:

125126

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

60422

show subpopulations

African (AFR)

AF:

0.0000654

AC:

AN:

30592

American (AMR)

AF:

0.0000851

AC:

AN:

11754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3156

East Asian (EAS)

AF:

0.00

AC:

AN:

4974

South Asian (SAS)

AF:

0.000236

AC:

AN:

4236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

256

European-Non Finnish (NFE)

AF:

0.0000167

AC:

AN:

59840

Other (OTH)

AF:

0.00

AC:

AN:

1750

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000415

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:8

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

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

INPP5E-related disorder

Pathogenic:1

Feb 01, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Feb 28, 2018

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joubert syndrome

Pathogenic:1

Sep 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is present in population databases (rs121918130, gnomAD 0.02%). 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. ClinVar contains an entry for this variant (Variation ID: 400). 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. Experimental studies have shown that this missense change affects INPP5E function (PMID: 19668216). 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. For these reasons, this variant has been classified as Pathogenic. 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). -

MORM syndrome;C4551568:Joubert syndrome 1

Pathogenic:1

Aug 22, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Pathogenic:1

Jul 11, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, 31964843, 36460718, 33749171, 23386033, 15786477, 30755392, 34188062) -

Joubert syndrome and related disorders

Pathogenic:1

May 31, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Joubert syndrome 1

Pathogenic:1

Sep 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

(source)

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

PhyloP100

4.1

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

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over