chr9-136432582-A-G

Position:

chr9-136432582-A-G

Variant summary

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

The NM_019892.6(INPP5E):c.1284T>C(p.Gly428=) 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 1,540,556 control chromosomes in the GnomAD database, including 151,687 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 13778 hom., cov: 32)

Exomes 𝑓: 0.44 ( 137909 hom. )

Consequence

INPP5E
NM_019892.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.92

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:

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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=-0.83).

BP6

Variant 9-136432582-A-G is Benign according to our data. Variant chr9-136432582-A-G is described in ClinVar as [Benign]. Clinvar id is 129266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136432582-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.92 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.518 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.1284T>C	p.Gly428=	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.1284T>C	p.Gly428=	synonymous_variant	6/10	1	NM_019892.6	ENSP00000360777	P1	Q9NRR6-1
INPP5E	ENST00000676019.1 linkuse as main transcript	c.1182T>C	p.Gly394=	synonymous_variant	6/10			ENSP00000501984		Q9NRR6-2

Frequencies

GnomAD3 genomes

AF:

0.421

AC:

63907

AN:

151890

Hom.:

13748

Cov.:

show subpopulations

Gnomad AFR

AF:

0.399

Gnomad AMI

AF:

0.391

Gnomad AMR

AF:

0.527

Gnomad ASJ

AF:

0.451

Gnomad EAS

AF:

0.207

Gnomad SAS

AF:

0.327

Gnomad FIN

AF:

0.326

Gnomad MID

AF:

0.414

Gnomad NFE

AF:

0.446

Gnomad OTH

AF:

0.439

GnomAD3 exomes

AF:

0.421

AC:

65329

AN:

155342

Hom.:

14628

AF XY:

0.409

AC XY:

33493

AN XY:

81884

show subpopulations

Gnomad AFR exome

AF:

0.395

Gnomad AMR exome

AF:

0.566

Gnomad ASJ exome

AF:

0.439

Gnomad EAS exome

AF:

0.194

Gnomad SAS exome

AF:

0.338

Gnomad FIN exome

AF:

0.334

Gnomad NFE exome

AF:

0.456

Gnomad OTH exome

AF:

0.434

GnomAD4 exome

AF:

0.441

AC:

611967

AN:

1388546

Hom.:

137909

Cov.:

AF XY:

0.437

AC XY:

299396

AN XY:

685382

show subpopulations

Gnomad4 AFR exome

AF:

0.395

Gnomad4 AMR exome

AF:

0.566

Gnomad4 ASJ exome

AF:

0.443

Gnomad4 EAS exome

AF:

0.226

Gnomad4 SAS exome

AF:

0.334

Gnomad4 FIN exome

AF:

0.336

Gnomad4 NFE exome

AF:

0.458

Gnomad4 OTH exome

AF:

0.428

GnomAD4 genome

AF:

0.421

AC:

63986

AN:

152010

Hom.:

13778

Cov.:

AF XY:

0.414

AC XY:

30795

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.400

Gnomad4 AMR

AF:

0.528

Gnomad4 ASJ

AF:

0.451

Gnomad4 EAS

AF:

0.206

Gnomad4 SAS

AF:

0.327

Gnomad4 FIN

AF:

0.326

Gnomad4 NFE

AF:

0.446

Gnomad4 OTH

AF:

0.439

Alfa

AF:

0.446

Hom.:

15277

Bravo

AF:

0.436

Asia WGS

AF:

0.320

AC:

1112

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

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:2

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

MORM syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

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

-0.83

CADD

Benign

0.13

DANN

Benign

0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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