rs10781542

Variant summary

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

The NM_019892.6(INPP5E):c.1248T>C(p.Thr416=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,612,540 control chromosomes in the GnomAD database, including 158,937 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 13784 hom., cov: 33)

Exomes 𝑓: 0.44 ( 145153 hom. )

Consequence

INPP5E
NM_019892.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.160

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=-0.53).

BP6

Variant 9-136432987-A-G is Benign according to our data. Variant chr9-136432987-A-G is described in ClinVar as [Benign]. Clinvar id is 129265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136432987-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.16 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6 linkuse as main transcript	c.1248T>C	p.Thr416=	synonymous_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.1248T>C	p.Thr416=	synonymous_variant	5/10	1	NM_019892.6	P1	Q9NRR6-1
INPP5E	ENST00000676019.1 linkuse as main transcript	c.1146T>C	p.Thr382=	synonymous_variant	5/10				Q9NRR6-2

Frequencies

GnomAD3 genomes

AF:

0.421

AC:

63929

AN:

151936

Hom.:

13754

Cov.:

show subpopulations

Gnomad AFR

AF:

0.398

Gnomad AMI

AF:

0.389

Gnomad AMR

AF:

0.527

Gnomad ASJ

AF:

0.450

Gnomad EAS

AF:

0.206

Gnomad SAS

AF:

0.328

Gnomad FIN

AF:

0.327

Gnomad MID

AF:

0.415

Gnomad NFE

AF:

0.446

Gnomad OTH

AF:

0.442

GnomAD3 exomes

AF:

0.420

AC:

104353

AN:

248560

Hom.:

23151

AF XY:

0.411

AC XY:

55431

AN XY:

134822

show subpopulations

Gnomad AFR exome

AF:

0.391

Gnomad AMR exome

AF:

0.570

Gnomad ASJ exome

AF:

0.440

Gnomad EAS exome

AF:

0.190

Gnomad SAS exome

AF:

0.340

Gnomad FIN exome

AF:

0.333

Gnomad NFE exome

AF:

0.451

Gnomad OTH exome

AF:

0.435

GnomAD4 exome

AF:

0.441

AC:

644336

AN:

1460486

Hom.:

145153

Cov.:

AF XY:

0.437

AC XY:

317514

AN XY:

726490

show subpopulations

Gnomad4 AFR exome

AF:

0.396

Gnomad4 AMR exome

AF:

0.570

Gnomad4 ASJ exome

AF:

0.443

Gnomad4 EAS exome

AF:

0.222

Gnomad4 SAS exome

AF:

0.336

Gnomad4 FIN exome

AF:

0.338

Gnomad4 NFE exome

AF:

0.459

Gnomad4 OTH exome

AF:

0.429

GnomAD4 genome

AF:

0.421

AC:

64008

AN:

152054

Hom.:

13784

Cov.:

AF XY:

0.414

AC XY:

30786

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.398

Gnomad4 AMR

AF:

0.528

Gnomad4 ASJ

AF:

0.450

Gnomad4 EAS

AF:

0.206

Gnomad4 SAS

AF:

0.328

Gnomad4 FIN

AF:

0.327

Gnomad4 NFE

AF:

0.446

Gnomad4 OTH

AF:

0.441

Alfa

AF:

0.447

Hom.:

19615

Bravo

AF:

0.436

Asia WGS

AF:

0.319

AC:

1111

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Joubert syndrome 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
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. -

MORM syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Familial aplasia of the vermis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

Cadd

Benign

Dann

Benign

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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