rs863225201

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_019892.6(INPP5E):c.1162G>T(p.Val388Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000174 in 1,611,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

INPP5E
NM_019892.6 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 5.51

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_019892.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.828

PP5

Variant 9-136433073-C-A is Pathogenic according to our data. Variant chr9-136433073-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217663.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}. Variant chr9-136433073-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6 linkuse as main transcript	c.1162G>T	p.Val388Leu	missense_variant, splice_region_variant	5/10	ENST00000371712.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5E	ENST00000371712.4 linkuse as main transcript	c.1162G>T	p.Val388Leu	missense_variant, splice_region_variant	5/10	1	NM_019892.6	P1	Q9NRR6-1
INPP5E	ENST00000676019.1 linkuse as main transcript	c.1060G>T	p.Val354Leu	missense_variant, splice_region_variant	5/10				Q9NRR6-2

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150760

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000249

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250054

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135604

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1460764

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726692

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150760

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73640

show subpopulations

Gnomad4 AFR

AF:

0.0000249

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial aplasia of the vermis

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Feb 23, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 16, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 388 of the INPP5E protein (p.Val388Leu). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with Joubert syndrome and related disorders and/or retinitis pigmentosa (PMID: 26092869; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 217663). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 30, 2019

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26092869) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.43

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.83

MetaSVM

Pathogenic

0.82

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.9

REVEL

Pathogenic

0.72

Sift

Uncertain

0.027

Sift4G

Benign

0.11

Polyphen

0.028

Vest4

0.87

MutPred

0.63

Loss of sheet (P = 0.0817);

MVP

0.97

MPC

0.39

ClinPred

0.72

GERP RS

4.8

Varity_R

0.40

gMVP

0.73

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