9-136434050-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP5

The NM_019892.6(INPP5E):c.1021G>A(p.Gly341Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000151 in 1,456,540 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G341D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

INPP5E
NM_019892.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 4.20

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

PP5

Variant 9-136434050-C-T is Pathogenic according to our data. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661. Variant chr9-136434050-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 217661.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6 link	c.1021G>A	p.Gly341Ser	missense_variant	Exon 3 of 10	ENST00000371712.4	NP_063945.2	Q9NRR6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INPP5E	ENST00000371712.4 link	c.1021G>A	p.Gly341Ser	missense_variant	Exon 3 of 10	1	NM_019892.6	ENSP00000360777.3	Q9NRR6-1
INPP5E	ENST00000676019.1 link	c.1021G>A	p.Gly341Ser	missense_variant	Exon 3 of 10			ENSP00000501984.1	Q9NRR6-2
INPP5E	ENST00000675256.1 link	c.250G>A	p.Gly84Ser	missense_variant	Exon 2 of 2			ENSP00000502517.1	A0A6Q8PH37
INPP5E	ENST00000674513.1 link	n.292G>A		non_coding_transcript_exon_variant	Exon 3 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000827

AC:

AN:

241952

AF XY:

0.0000152

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1456540

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

724268

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.00

AC:

AN:

44402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26034

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.00

AC:

AN:

85442

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

1110752

Other (OTH)

AF:

0.0000332

AC:

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Joubert syndrome

Pathogenic:2

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

May 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 341 of the INPP5E protein (p.Gly341Ser). This variant is present in population databases (rs780882740, gnomAD 0.002%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 26092869). ClinVar contains an entry for this variant (Variation ID: 217661). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on INPP5E protein function. For these reasons, this variant has been classified as Pathogenic. -

not provided

Uncertain:1

Mar 20, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Previously identified in individuals with Joubert syndrome who harbored a second INPP5E variant; however, segregation to determine the phase of the variants was not reported (PMID: 26092869); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23386033, 31964843, 26092869) -

Joubert syndrome 1

Uncertain:1

Nov 16, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

The heterozygous p.Gly341Ser variant in INPP5E was identified by our study in the compound heterozygous state, along with another variant of uncertain significance, in 1 individual with Joubert syndrome 1. The variant has been reported in 3 individuals of unknown ethnicity with Joubert syndrome 1 (PMID: 26092869), and has been identified in 0.002% (2/109550) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs780882740). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 217661) as pathogenic by UW Hindbrain Malformation Research Program, University of Washington. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of an individual heterozygous for this variant is highly specific for Joubert syndrome 1 based on unique phenotype consistent with disease. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP4 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

0.095

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.48

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-0.43

MutationAssessor

Benign

0.39

PhyloP100

4.2

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.54

Sift

Benign

0.51

Sift4G

Benign

0.26

Polyphen

0.69

Vest4

0.77

MutPred

0.42

Gain of disorder (P = 0.0907);

MVP

0.84

MPC

0.82

ClinPred

0.88

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.57

gMVP

0.85

Mutation Taster

=27/73

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over