NM_019892.6:c.1521C>T

Variant names:

Variant summary

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

The NM_019892.6(INPP5E):c.1521C>T(p.His507His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,585,362 control chromosomes in the GnomAD database, including 15,661 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1067 hom., cov: 26)

Exomes 𝑓: 0.13 ( 14594 hom. )

Consequence

INPP5E
NM_019892.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.37

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=-0.89).

BP6

Variant 9-136431852-G-A is Benign according to our data. Variant chr9-136431852-G-A is described in ClinVar as [Benign]. Clinvar id is 129268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136431852-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.37 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6 link	c.1521C>T	p.His507His	synonymous_variant	Exon 7 of 10	ENST00000371712.4	NP_063945.2	Q9NRR6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712.4 link	c.1521C>T	p.His507His	synonymous_variant	Exon 7 of 10	1	NM_019892.6	ENSP00000360777.3		Q9NRR6-1
INPP5E	ENST00000676019.1 link	c.1419C>T	p.His473His	synonymous_variant	Exon 7 of 10			ENSP00000501984.1		Q9NRR6-2

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

15216

AN:

144000

Hom.:

1059

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0360

Gnomad AMI

AF:

0.0718

Gnomad AMR

AF:

0.191

Gnomad ASJ

AF:

0.116

Gnomad EAS

AF:

0.146

Gnomad SAS

AF:

0.146

Gnomad FIN

AF:

0.0708

Gnomad MID

AF:

0.129

Gnomad NFE

AF:

0.128

Gnomad OTH

AF:

0.105

GnomAD3 exomes

AF:

0.142

AC:

34747

AN:

244852

Hom.:

2950

AF XY:

0.140

AC XY:

18672

AN XY:

133646

show subpopulations

Gnomad AFR exome

AF:

0.0350

Gnomad AMR exome

AF:

0.263

Gnomad ASJ exome

AF:

0.110

Gnomad EAS exome

AF:

0.146

Gnomad SAS exome

AF:

0.162

Gnomad FIN exome

AF:

0.0699

Gnomad NFE exome

AF:

0.131

Gnomad OTH exome

AF:

0.129

GnomAD4 exome

AF:

0.132

AC:

190900

AN:

1441254

Hom.:

14594

Cov.:

AF XY:

0.133

AC XY:

95186

AN XY:

716898

show subpopulations

Gnomad4 AFR exome

AF:

0.0296

Gnomad4 AMR exome

AF:

0.255

Gnomad4 ASJ exome

AF:

0.104

Gnomad4 EAS exome

AF:

0.135

Gnomad4 SAS exome

AF:

0.155

Gnomad4 FIN exome

AF:

0.0709

Gnomad4 NFE exome

AF:

0.133

Gnomad4 OTH exome

AF:

0.127

GnomAD4 genome

AF:

0.106

AC:

15243

AN:

144108

Hom.:

1067

Cov.:

AF XY:

0.105

AC XY:

7366

AN XY:

69902

show subpopulations

Gnomad4 AFR

AF:

0.0363

Gnomad4 AMR

AF:

0.191

Gnomad4 ASJ

AF:

0.116

Gnomad4 EAS

AF:

0.146

Gnomad4 SAS

AF:

0.146

Gnomad4 FIN

AF:

0.0708

Gnomad4 NFE

AF:

0.128

Gnomad4 OTH

AF:

0.104

Alfa

AF:

0.0982

Hom.:

267

Bravo

AF:

0.116

Asia WGS

AF:

0.146

AC:

503

AN:

3438

EpiCase

AF:

0.131

EpiControl

AF:

0.129

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 27, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Joubert syndrome 1

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MORM syndrome

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial aplasia of the vermis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.055

DANN

Benign

0.53

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