rs35498378

Positions:

Variant summary

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

The NM_019892.6(INPP5E):c.981C>T(p.Ala327Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,610,840 control chromosomes in the GnomAD database, including 488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 232 hom., cov: 33)

Exomes 𝑓: 0.011 ( 256 hom. )

Consequence

INPP5E
NM_019892.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.00100

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:

INPP5E (HGNC:):

INPP5E links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 9-136434090-G-A is Benign according to our data. Variant chr9-136434090-G-A is described in ClinVar as [Benign]. Clinvar id is 129278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136434090-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.001 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0949 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.981C>T	p.Ala327Ala	synonymous_variant	3/10	ENST00000371712.4	NP_063945.2	Q9NRR6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
INPP5E	ENST00000371712.4 linkuse as main transcript	c.981C>T	p.Ala327Ala	synonymous_variant	3/10	1	NM_019892.6	ENSP00000360777.3	Q9NRR6-1
INPP5E	ENST00000676019.1 linkuse as main transcript	c.981C>T	p.Ala327Ala	synonymous_variant	3/10			ENSP00000501984.1	Q9NRR6-2
INPP5E	ENST00000675256.1 linkuse as main transcript	c.210C>T	p.Ala70Ala	synonymous_variant	2/2			ENSP00000502517.1	A0A6Q8PH37
INPP5E	ENST00000674513.1 linkuse as main transcript	n.252C>T		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes

AF:

0.0341

AC:

5185

AN:

152150

Hom.:

232

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0974

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0215

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0103

Gnomad OTH

AF:

0.0334

GnomAD3 exomes

AF:

0.0134

AC:

3279

AN:

244786

Hom.:

AF XY:

0.0114

AC XY:

1512

AN XY:

133032

show subpopulations

Gnomad AFR exome

AF:

0.0989

Gnomad AMR exome

AF:

0.0108

Gnomad ASJ exome

AF:

0.00536

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.00170

Gnomad FIN exome

AF:

0.000904

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.0114

AC:

16555

AN:

1458572

Hom.:

256

Cov.:

AF XY:

0.0107

AC XY:

7789

AN XY:

725422

show subpopulations

Gnomad4 AFR exome

AF:

0.103

Gnomad4 AMR exome

AF:

0.0118

Gnomad4 ASJ exome

AF:

0.00591

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00149

Gnomad4 FIN exome

AF:

0.000779

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.0132

GnomAD4 genome

AF:

0.0341

AC:

5196

AN:

152268

Hom.:

232

Cov.:

AF XY:

0.0323

AC XY:

2402

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0974

Gnomad4 AMR

AF:

0.0214

Gnomad4 ASJ

AF:

0.00662

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.0103

Gnomad4 OTH

AF:

0.0331

Alfa

AF:

0.0153

Hom.:

Bravo

AF:

0.0382

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0121

EpiControl

AF:

0.0141

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.52

DANN

Benign

0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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