rs36064831

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_019892.6(INPP5E):c.603C>G(p.Ile201Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,611,706 control chromosomes in the GnomAD database, including 637 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 49 hom., cov: 33)

Exomes 𝑓: 0.024 ( 588 hom. )

Consequence

INPP5E
NM_019892.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.73

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015648305).

BP6

Variant 9-136438817-G-C is Benign according to our data. Variant chr9-136438817-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 129275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136438817-G-C is described in Lovd as [Benign]. Variant chr9-136438817-G-C is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6 link	c.603C>G	p.Ile201Met	missense_variant	Exon 1 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.603C>G	p.Ile201Met	missense_variant	Exon 1 of 10	1	NM_019892.6	ENSP00000360777.3	Q9NRR6-1
INPP5E	ENST00000676019.1 link	c.603C>G	p.Ile201Met	missense_variant	Exon 1 of 10			ENSP00000501984.1	Q9NRR6-2
INPP5E	ENST00000635815.1 link	n.1007C>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
INPP5E	ENST00000674513.1 link	n.-127C>G		upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.0186

AC:

2826

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00601

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0258

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00827

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0237

Gnomad OTH

AF:

0.0311

GnomAD3 exomes

AF:

0.0204

AC:

4912

AN:

241276

Hom.:

107

AF XY:

0.0208

AC XY:

2748

AN XY:

131908

show subpopulations

Gnomad AFR exome

AF:

0.00613

Gnomad AMR exome

AF:

0.0178

Gnomad ASJ exome

AF:

0.107

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00857

Gnomad FIN exome

AF:

0.00411

Gnomad NFE exome

AF:

0.0244

Gnomad OTH exome

AF:

0.0344

GnomAD4 exome

AF:

0.0236

AC:

34444

AN:

1459408

Hom.:

588

Cov.:

AF XY:

0.0237

AC XY:

17171

AN XY:

725974

show subpopulations

Gnomad4 AFR exome

AF:

0.00744

Gnomad4 AMR exome

AF:

0.0186

Gnomad4 ASJ exome

AF:

0.108

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00888

Gnomad4 FIN exome

AF:

0.00537

Gnomad4 NFE exome

AF:

0.0246

Gnomad4 OTH exome

AF:

0.0284

GnomAD4 genome

AF:

0.0185

AC:

2825

AN:

152298

Hom.:

Cov.:

AF XY:

0.0184

AC XY:

1370

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00601

Gnomad4 AMR

AF:

0.0258

Gnomad4 ASJ

AF:

0.111

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00827

Gnomad4 FIN

AF:

0.00358

Gnomad4 NFE

AF:

0.0237

Gnomad4 OTH

AF:

0.0307

Alfa

AF:

0.0309

Hom.:

Bravo

AF:

0.0217

TwinsUK

AF:

0.0245

AC:

ALSPAC

AF:

0.0210

AC:

ESP6500AA

AF:

0.00592

AC:

ESP6500EA

AF:

0.0300

AC:

258

ExAC

AF:

0.0187

AC:

2256

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 15, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Nov 13, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joubert syndrome 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Familial aplasia of the vermis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

0.50

DANN

Benign

0.71

DEOGEN2

Benign

0.043

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.32

MutationAssessor

Benign

-0.69

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.50

REVEL

Benign

0.21

Sift

Benign

0.26

Sift4G

Benign

0.23

Polyphen

0.033

Vest4

0.011

MPC

0.33

ClinPred

0.0044

GERP RS

-6.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.13

gMVP

0.36

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