9-136433182-G-A

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

14
4
1

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

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
INPP5ENM_019892.6 linkc.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
INPP5EENST00000371712.4 linkc.1132C>T p.Arg378Cys missense_variant Exon 4 of 10 1 NM_019892.6 ENSP00000360777.3 Q9NRR6-1
INPP5EENST00000676019.1 linkc.1035-5C>T splice_region_variant, intron_variant Intron 3 of 9 ENSP00000501984.1 Q9NRR6-2

Frequencies

GnomAD3 genomes
AF:
0.0000400
AC:
5
AN:
125126
Hom.:
0
Cov.:
32
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:
8
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:
20
AN:
1179208
Hom.:
0
Cov.:
35
AF XY:
0.0000169
AC XY:
10
AN XY:
590820
show subpopulations
African (AFR)
AF:
0.0000820
AC:
2
AN:
24386
American (AMR)
AF:
0.0000263
AC:
1
AN:
38044
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
21880
East Asian (EAS)
AF:
0.0000270
AC:
1
AN:
37034
South Asian (SAS)
AF:
0.0000123
AC:
1
AN:
81378
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
35066
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5192
European-Non Finnish (NFE)
AF:
0.0000135
AC:
12
AN:
887316
Other (OTH)
AF:
0.0000613
AC:
3
AN:
48912
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
5
AN:
125126
Hom.:
0
Cov.:
32
AF XY:
0.0000331
AC XY:
2
AN XY:
60422
show subpopulations
African (AFR)
AF:
0.0000654
AC:
2
AN:
30592
American (AMR)
AF:
0.0000851
AC:
1
AN:
11754
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3156
East Asian (EAS)
AF:
0.00
AC:
0
AN:
4974
South Asian (SAS)
AF:
0.000236
AC:
1
AN:
4236
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
7752
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
256
European-Non Finnish (NFE)
AF:
0.0000167
AC:
1
AN:
59840
Other (OTH)
AF:
0.00
AC:
0
AN:
1750
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.495
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
0
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.000683
AC:
3
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000413
AC:
5

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
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.88
D
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.80
D
MutationAssessor
Pathogenic
4.2
H
PhyloP100
4.1
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-7.4
D
REVEL
Pathogenic
0.84
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.97
MVP
0.97
MPC
1.2
ClinPred
1.0
D
GERP RS
3.0
Varity_R
0.92
gMVP
0.92
Mutation Taster
=15/85
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918130; hg19: chr9-139327634; API