rs10870182

chr9-136430288-C-Gchr9-136430288-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_019892.6(INPP5E):c.1791G>C(p.Pro597=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00835 in 1,551,406 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P597P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0049 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0087 (81 hom.)
• Consequence: INPP5E NM_019892.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -4.81

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 9-136430288-C-G is Benign according to our data. Variant chr9-136430288-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129271.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=1, Uncertain_significance=1}. Variant chr9-136430288-C-G is described in Lovd as [Benign]. Variant chr9-136430288-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.81 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00494 (753/152322) while in subpopulation NFE AF= 0.00879 (598/68014). AF 95% confidence interval is 0.00821. There are 2 homozygotes in gnomad4. There are 334 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6	c.1791G>C	p.Pro597=	synonymous_variant	9/10	ENST00000371712.4
INPP5E	NM_001318502.2	c.1788G>C	p.Pro596=	synonymous_variant	9/10
INPP5E	XM_017014926.2	c.1791G>C	p.Pro597=	synonymous_variant	9/10
INPP5E	XM_047423603.1	c.1788G>C	p.Pro596=	synonymous_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5E	ENST00000371712.4	c.1791G>C	p.Pro597=	synonymous_variant	9/10	1	NM_019892.6	P1
INPP5E	ENST00000676019.1	c.1689G>C	p.Pro563=	synonymous_variant	9/10
INPP5E	ENST00000674693.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00495 AC: 753 AN: 152204 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00879

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00417 AC: 653 AN: 156470 Hom.: 6 AF XY: 0.00407 AC XY: 335 AN XY: 82306

Gnomad AFR exome AF: 0.00251

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.000469

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00145

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.00848

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00872 AC: 12207 AN: 1399084 Hom.: 81 Cov.: 36 AF XY: 0.00834 AC XY: 5754 AN XY: 690040

Gnomad4 AFR exome AF: 0.00174

Gnomad4 AMR exome AF: 0.00205

Gnomad4 ASJ exome AF: 0.000675

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00173

Gnomad4 FIN exome AF: 0.00127

Gnomad4 NFE exome AF: 0.0105

Gnomad4 OTH exome AF: 0.00912

GnomAD4 genome AF: 0.00494 AC: 753 AN: 152322 Hom.: 2 Cov.: 33 AF XY: 0.00448 AC XY: 334 AN XY: 74478

Gnomad4 AFR AF: 0.00209

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00879

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00139 Hom.: 128

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 11, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 22, 2013	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	INPP5E: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Joubert syndrome 1 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Familial aplasia of the vermis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.037
Dann	Benign	0.60

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: rs10870182; hg19: chr9-139324740;