9-136431131-G-A

Position:

chr9-136431131-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_019892.6(INPP5E):c.1550-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,575,526 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0010 ( 16 hom. )

Consequence

INPP5E
NM_019892.6 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.336

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 9-136431131-G-A is Benign according to our data. Variant chr9-136431131-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00124 (187/151408) while in subpopulation AMR AF= 0.00808 (122/15106). AF 95% confidence interval is 0.00691. There are 2 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
INPP5E	NM_019892.6 linkuse as main transcript	c.1550-14C>T	intron_variant	ENST00000371712.4	NP_063945.2	Q9NRR6-1
INPP5E	NM_001318502.2 linkuse as main transcript	c.1547-14C>T	intron_variant		NP_001305431.1	Q9NRR6
INPP5E	XM_017014926.2 linkuse as main transcript	c.1550-14C>T	intron_variant		XP_016870415.1
INPP5E	XM_047423603.1 linkuse as main transcript	c.1547-14C>T	intron_variant		XP_047279559.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	UniProt
INPP5E	ENST00000371712.4 linkuse as main transcript	c.1550-14C>T	intron_variant		1	NM_019892.6	ENSP00000360777.3	Q9NRR6-1
INPP5E	ENST00000676019.1 linkuse as main transcript	c.1448-14C>T	intron_variant				ENSP00000501984.1	Q9NRR6-2
INPP5E	ENST00000674693.1 linkuse as main transcript	n.53C>T	non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

184

AN:

151292

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000267

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00789

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00117

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00248

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000192

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.00360

AC:

890

AN:

247214

Hom.:

AF XY:

0.00294

AC XY:

395

AN XY:

134170

show subpopulations

Gnomad AFR exome

AF:

0.000441

Gnomad AMR exome

AF:

0.0202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000985

Gnomad SAS exome

AF:

0.00168

Gnomad FIN exome

AF:

0.00362

Gnomad NFE exome

AF:

0.000171

Gnomad OTH exome

AF:

0.00431

GnomAD4 exome

AF:

0.00100

AC:

1429

AN:

1424118

Hom.:

Cov.:

AF XY:

0.000919

AC XY:

653

AN XY:

710630

show subpopulations

Gnomad4 AFR exome

AF:

0.000245

Gnomad4 AMR exome

AF:

0.0184

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00188

Gnomad4 SAS exome

AF:

0.00131

Gnomad4 FIN exome

AF:

0.00290

Gnomad4 NFE exome

AF:

0.000155

Gnomad4 OTH exome

AF:

0.00173

GnomAD4 genome

AF:

0.00124

AC:

187

AN:

151408

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

110

AN XY:

73946

show subpopulations

Gnomad4 AFR

AF:

0.000267

Gnomad4 AMR

AF:

0.00808

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00117

Gnomad4 SAS

AF:

0.000831

Gnomad4 FIN

AF:

0.00248

Gnomad4 NFE

AF:

0.000192

Gnomad4 OTH

AF:

0.00238

Alfa

AF:

0.00100

Hom.:

Bravo

AF:

0.00295

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 04, 2016

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. -

INPP5E-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely 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 12, 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

-0.84

CADD

Benign

DANN

Benign

0.38

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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