rs35774078

Positions:

chr9-136432507-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000371712.4(INPP5E):c.1359C>T(p.Pro453=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0313 in 1,550,870 control chromosomes in the GnomAD database, including 1,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.052 ( 382 hom., cov: 32)

Exomes 𝑓: 0.029 ( 929 hom. )

Consequence

INPP5E
ENST00000371712.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -6.71

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 9-136432507-G-A is Benign according to our data. Variant chr9-136432507-G-A is described in ClinVar as [Benign]. Clinvar id is 129267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136432507-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-6.71 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INPP5E	NM_019892.6 linkuse as main transcript	c.1359C>T	p.Pro453=	synonymous_variant	6/10	ENST00000371712.4	NP_063945.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712.4 linkuse as main transcript	c.1359C>T	p.Pro453=	synonymous_variant	6/10	1	NM_019892.6	ENSP00000360777	P1	Q9NRR6-1
INPP5E	ENST00000676019.1 linkuse as main transcript	c.1257C>T	p.Pro419=	synonymous_variant	6/10			ENSP00000501984		Q9NRR6-2

Frequencies

GnomAD3 genomes

AF:

0.0519

AC:

7900

AN:

152176

Hom.:

381

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0497

Gnomad ASJ

AF:

0.112

Gnomad EAS

AF:

0.00519

Gnomad SAS

AF:

0.00890

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0264

Gnomad OTH

AF:

0.0636

GnomAD3 exomes

AF:

0.0322

AC:

5100

AN:

158226

Hom.:

161

AF XY:

0.0302

AC XY:

2525

AN XY:

83496

show subpopulations

Gnomad AFR exome

AF:

0.114

Gnomad AMR exome

AF:

0.0315

Gnomad ASJ exome

AF:

0.109

Gnomad EAS exome

AF:

0.00699

Gnomad SAS exome

AF:

0.00895

Gnomad FIN exome

AF:

0.00404

Gnomad NFE exome

AF:

0.0294

Gnomad OTH exome

AF:

0.0478

GnomAD4 exome

AF:

0.0291

AC:

40640

AN:

1398576

Hom.:

929

Cov.:

AF XY:

0.0287

AC XY:

19787

AN XY:

690040

show subpopulations

Gnomad4 AFR exome

AF:

0.119

Gnomad4 AMR exome

AF:

0.0335

Gnomad4 ASJ exome

AF:

0.109

Gnomad4 EAS exome

AF:

0.00469

Gnomad4 SAS exome

AF:

0.00946

Gnomad4 FIN exome

AF:

0.00551

Gnomad4 NFE exome

AF:

0.0266

Gnomad4 OTH exome

AF:

0.0435

GnomAD4 genome

AF:

0.0520

AC:

7914

AN:

152294

Hom.:

382

Cov.:

AF XY:

0.0510

AC XY:

3799

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.112

Gnomad4 AMR

AF:

0.0496

Gnomad4 ASJ

AF:

0.112

Gnomad4 EAS

AF:

0.00501

Gnomad4 SAS

AF:

0.00890

Gnomad4 FIN

AF:

0.00358

Gnomad4 NFE

AF:

0.0264

Gnomad4 OTH

AF:

0.0634

Alfa

AF:

0.0426

Hom.:

118

Bravo

AF:

0.0601

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2014	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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Joubert syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial aplasia of the vermis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.25

DANN

Benign

0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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