rs5901103

chr9-136438597-GCCCT-Gchr9-136438597-GCCCT-GCCCTCCCT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_019892.6(INPP5E):c.812+7_812+10del variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.927 in 1,550,996 control chromosomes in the GnomAD database, including 667,162 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67416 hom., cov: 0)
  • Exomes 𝑓: 0.93 (599746 hom.)
• Consequence: INPP5E NM_019892.6 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.21

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 9-136438597-GCCCT-G is Benign according to our data. Variant chr9-136438597-GCCCT-G is described in ClinVar as [Benign]. Clinvar id is 261203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136438597-GCCCT-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6	c.812+7_812+10del		splice_region_variant, intron_variant		ENST00000371712.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5E	ENST00000371712.4	c.812+7_812+10del		splice_region_variant, intron_variant		1	NM_019892.6	P1
INPP5E	ENST00000676019.1	c.812+7_812+10del		splice_region_variant, intron_variant
INPP5E	ENST00000635815.1	n.1223_1226del		non_coding_transcript_exon_variant	1/1
INPP5E	ENST00000674513.1	n.83+7_83+10del		splice_region_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.941 AC: 143010 AN: 151978 Hom.: 67351 Cov.: 0

Gnomad AFR AF: 0.985

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.948

Gnomad ASJ AF: 0.919

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.935

Gnomad FIN AF: 0.886

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.921

Gnomad OTH AF: 0.924

GnomAD3 exomes AF: 0.934 AC: 139958 AN: 149796 Hom.: 65449 AF XY: 0.932 AC XY: 75529 AN XY: 81070

Gnomad AFR exome AF: 0.988

Gnomad AMR exome AF: 0.961

Gnomad ASJ exome AF: 0.915

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.927

Gnomad FIN exome AF: 0.889

Gnomad NFE exome AF: 0.922

Gnomad OTH exome AF: 0.927

GnomAD4 exome AF: 0.926 AC: 1294939 AN: 1398902 Hom.: 599746 AF XY: 0.926 AC XY: 639123 AN XY: 690482

Gnomad4 AFR exome AF: 0.988

Gnomad4 AMR exome AF: 0.959

Gnomad4 ASJ exome AF: 0.915

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.929

Gnomad4 FIN exome AF: 0.892

Gnomad4 NFE exome AF: 0.922

Gnomad4 OTH exome AF: 0.928

GnomAD4 genome AF: 0.941 AC: 143134 AN: 152094 Hom.: 67416 Cov.: 0 AF XY: 0.940 AC XY: 69869 AN XY: 74338

Gnomad4 AFR AF: 0.985

Gnomad4 AMR AF: 0.948

Gnomad4 ASJ AF: 0.919

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.935

Gnomad4 FIN AF: 0.886

Gnomad4 NFE AF: 0.921

Gnomad4 OTH AF: 0.926

Alfa AF: 0.935 Hom.: 12017

Bravo AF: 0.946

Asia WGS AF: 0.969 AC: 3366 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 13, 2015	- -

Familial aplasia of the vermis Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

MORM syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 01, 2018

- -

Joubert syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs5901103; hg19: chr9-139333049;