rs121918128

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_019892.6(INPP5E):c.1688G>A(p.Arg563His) variant causes a missense change. The variant allele was found at a frequency of 0.0000148 in 1,556,350 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 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

INPP5E
NM_019892.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.99

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

PP5

Variant 9-136430391-C-T is Pathogenic according to our data. Variant chr9-136430391-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 398.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
INPP5E	NM_019892.6 link	c.1688G>A	p.Arg563His	missense_variant	Exon 9 of 10	ENST00000371712.4	NP_063945.2	Q9NRR6-1
INPP5E	NM_001318502.2 link	c.1685G>A	p.Arg562His	missense_variant	Exon 9 of 10		NP_001305431.1	Q9NRR6
INPP5E	XM_017014926.2 link	c.1688G>A	p.Arg563His	missense_variant	Exon 9 of 10		XP_016870415.1
INPP5E	XM_047423603.1 link	c.1685G>A	p.Arg562His	missense_variant	Exon 9 of 10		XP_047279559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INPP5E	ENST00000371712.4 link	c.1688G>A	p.Arg563His	missense_variant	Exon 9 of 10	1	NM_019892.6	ENSP00000360777.3	Q9NRR6-1
INPP5E	ENST00000676019.1 link	c.1586G>A	p.Arg529His	missense_variant	Exon 9 of 10			ENSP00000501984.1	Q9NRR6-2
INPP5E	ENST00000674693.1 link	n.205G>A		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152234

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000614

AC:

AN:

162982

Hom.:

AF XY:

0.0000116

AC XY:

AN XY:

85978

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:

0.0000432

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1404116

Hom.:

Cov.:

AF XY:

0.0000202

AC XY:

AN XY:

692912

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000271

Gnomad4 SAS exome

AF:

0.0000377

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000166

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000922

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Joubert syndrome 1

Pathogenic:2

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PP1,PM3,PM2,PM5 -

Sep 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Joubert syndrome and related disorders

Pathogenic:1

Jul 18, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: INPP5E c.1688G>A (p.Arg563His) results in a non-conservative amino acid change located in the Inositol polyphosphate-related phosphatase (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 6.1e-06 in 162982 control chromosomes. c.1688G>A has been reported in the literature in at-least two individuals affected with Joubert Syndrome (Bielas_2009, Travaglini_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 50% of normal INPP5E activity in HEK29T cells (Bielas_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19668216, 23386033). ClinVar contains an entry for this variant (Variation ID: 398). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.47

MutationAssessor

Uncertain

2.4

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.91

MutPred

0.77

Loss of MoRF binding (P = 0.0382);

MVP

0.95

MPC

1.2

ClinPred

0.98

GERP RS

5.3

Varity_R

0.75

gMVP

0.64

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