rs143552175

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_019892.6(INPP5E):c.1770C>T(p.Leu590Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,551,804 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0062 ( 8 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 9 hom. )

Consequence

INPP5E
NM_019892.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.603

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 9-136430309-G-A is Benign according to our data. Variant chr9-136430309-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136430309-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.603 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0062 (944/152364) while in subpopulation AFR AF= 0.021 (872/41584). AF 95% confidence interval is 0.0198. There are 8 homozygotes in gnomad4. There are 458 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INPP5E	NM_019892.6 link	c.1770C>T	p.Leu590Leu	synonymous_variant	9/10	ENST00000371712.4	NP_063945.2	Q9NRR6-1
INPP5E	NM_001318502.2 link	c.1767C>T	p.Leu589Leu	synonymous_variant	9/10		NP_001305431.1	Q9NRR6
INPP5E	XM_017014926.2 link	c.1770C>T	p.Leu590Leu	synonymous_variant	9/10		XP_016870415.1
INPP5E	XM_047423603.1 link	c.1767C>T	p.Leu589Leu	synonymous_variant	9/10		XP_047279559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
INPP5E	ENST00000371712.4 link	c.1770C>T	p.Leu590Leu	synonymous_variant	9/10	1	NM_019892.6	ENSP00000360777.3	Q9NRR6-1
INPP5E	ENST00000676019.1 link	c.1668C>T	p.Leu556Leu	synonymous_variant	9/10			ENSP00000501984.1	Q9NRR6-2
INPP5E	ENST00000674693.1 link	n.*26C>T		downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.00617

AC:

940

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0209

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00379

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00138

AC:

217

AN:

156866

Hom.:

AF XY:

0.000957

AC XY:

AN XY:

82516

show subpopulations

Gnomad AFR exome

AF:

0.0188

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000165

Gnomad OTH exome

AF:

0.00135

GnomAD4 exome

AF:

0.000550

AC:

770

AN:

1399440

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

315

AN XY:

690248

show subpopulations

Gnomad4 AFR exome

AF:

0.0193

Gnomad4 AMR exome

AF:

0.00165

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000379

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000371

Gnomad4 OTH exome

AF:

0.00155

GnomAD4 genome

AF:

0.00620

AC:

944

AN:

152364

Hom.:

Cov.:

AF XY:

0.00615

AC XY:

458

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.0210

Gnomad4 AMR

AF:

0.00379

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00231

Hom.:

Bravo

AF:

0.00722

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 16, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Familial aplasia of the vermis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

8.8

DANN

Benign

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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