rs13297509

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_019892.6(INPP5E):c.1543C>T(p.Arg515Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,524,546 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 0.0000082 ( 0 hom., cov: 21)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

INPP5E
NM_019892.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.18

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 Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

PP5

Variant 9-136431830-G-A is Pathogenic according to our data. Variant chr9-136431830-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136431830-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INPP5E	NM_019892.6 linkuse as main transcript	c.1543C>T	p.Arg515Trp	missense_variant	7/10	ENST00000371712.4	NP_063945.2	Q9NRR6-1
INPP5E	NM_001318502.2 linkuse as main transcript	c.1540C>T	p.Arg514Trp	missense_variant	7/10		NP_001305431.1	Q9NRR6
INPP5E	XM_017014926.2 linkuse as main transcript	c.1543C>T	p.Arg515Trp	missense_variant	7/10		XP_016870415.1
INPP5E	XM_047423603.1 linkuse as main transcript	c.1540C>T	p.Arg514Trp	missense_variant	7/10		XP_047279559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712.4 linkuse as main transcript	c.1543C>T	p.Arg515Trp	missense_variant	7/10	1	NM_019892.6	ENSP00000360777.3		Q9NRR6-1
INPP5E	ENST00000676019.1 linkuse as main transcript	c.1441C>T	p.Arg481Trp	missense_variant	7/10			ENSP00000501984.1		Q9NRR6-2

Frequencies

GnomAD3 genomes

AF:

0.00000818

AC:

AN:

122306

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000170

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000377

AC:

AN:

238850

Hom.:

AF XY:

0.0000534

AC XY:

AN XY:

131146

show subpopulations

Gnomad AFR exome

AF:

0.000342

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000591

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000280

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000128

AC:

AN:

1402240

Hom.:

Cov.:

AF XY:

0.0000172

AC XY:

AN XY:

697262

show subpopulations

Gnomad4 AFR exome

AF:

0.0000630

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000305

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000139

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000818

AC:

AN:

122306

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

58406

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000170

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000203

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000166

AC:

EpiCase

AF:

0.0000549

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Joubert syndrome 1

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2009	- -
Pathogenic, criteria provided, single submitter	research	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2024	PM3,PS3,PM2,PP4,PP1 -

MORM syndrome;C4551568:Joubert syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 15, 2024

- -

Familial aplasia of the vermis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 24, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 515 of the INPP5E protein (p.Arg515Trp). This variant is present in population databases (rs13297509, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of Joubert syndrome or retinitis pigmentosa (PMID: 19668216, 27081510, 28559085; Invitae). ClinVar contains an entry for this variant (Variation ID: 397). 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. Experimental studies have shown that this missense change affects INPP5E function (PMID: 19668216). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.83

Eigen

Benign

-0.90

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.47

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.37

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.73

MutPred

0.50

Loss of disorder (P = 0.0349);

MVP

0.84

MPC

0.79

ClinPred

0.35

GERP RS

-4.3

Varity_R

0.28

gMVP

0.59

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