9-136430288-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_019892.6(INPP5E):c.1791G>A(p.Pro597=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,551,346 control chromosomes in the GnomAD database, including 15,270 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P597P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1173 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14097 hom.)
• Consequence: INPP5E NM_019892.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 9-136430288-C-T is Benign according to our data. Variant chr9-136430288-C-T is described in ClinVar as [Benign]. Clinvar id is 129270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136430288-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.81 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17171 AN: 152182 Hom.: 1164 Cov.: 33

Gnomad AFR AF: 0.0541

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.0728

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.147 AC: 22927 AN: 156470 Hom.: 2011 AF XY: 0.144 AC XY: 11892 AN XY: 82306

Gnomad AFR exome AF: 0.0528

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.152

Gnomad SAS exome AF: 0.164

Gnomad FIN exome AF: 0.0670

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.137 AC: 191943 AN: 1399046 Hom.: 14097 Cov.: 36 AF XY: 0.138 AC XY: 94986 AN XY: 690026

Gnomad4 AFR exome AF: 0.0497

Gnomad4 AMR exome AF: 0.257

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.138

Gnomad4 SAS exome AF: 0.161

Gnomad4 FIN exome AF: 0.0728

Gnomad4 NFE exome AF: 0.138

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.113 AC: 17204 AN: 152300 Hom.: 1173 Cov.: 33 AF XY: 0.113 AC XY: 8397 AN XY: 74466

Gnomad4 AFR AF: 0.0544

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.0728

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.115

Alfa AF: 0.0805 Hom.: 128

Bravo AF: 0.123

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	GeneDx	Feb 27, 2014	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. -

Joubert syndrome 1 Benign:2

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

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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.33
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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; COSMIC: COSV65496036;