rs10870199

chr9-136434099-T-C

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.972A>G(p.Pro324=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,609,748 control chromosomes in the GnomAD database, including 16,710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1177 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15533 hom.)
• Consequence: INPP5E NM_019892.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.89

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=-0.92).
• BP6: Variant 9-136434099-T-C is Benign according to our data. Variant chr9-136434099-T-C is described in ClinVar as [Benign]. Clinvar id is 129277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136434099-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6	c.972A>G	p.Pro324=	synonymous_variant	3/10	ENST00000371712.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5E	ENST00000371712.4	c.972A>G	p.Pro324=	synonymous_variant	3/10	1	NM_019892.6	P1
INPP5E	ENST00000676019.1	c.972A>G	p.Pro324=	synonymous_variant	3/10
INPP5E	ENST00000675256.1	c.204A>G	p.Pro68=	synonymous_variant	2/2
INPP5E	ENST00000674513.1	n.243A>G		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16345 AN: 152126 Hom.: 1169 Cov.: 33

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.0769

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.0737

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.114

GnomAD3 exomes AF: 0.144 AC: 35124 AN: 243562 Hom.: 2963 AF XY: 0.142 AC XY: 18822 AN XY: 132450

Gnomad AFR exome AF: 0.0267

Gnomad AMR exome AF: 0.263

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.154

Gnomad SAS exome AF: 0.163

Gnomad FIN exome AF: 0.0687

Gnomad NFE exome AF: 0.135

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.140 AC: 204771 AN: 1457504 Hom.: 15533 Cov.: 33 AF XY: 0.141 AC XY: 101996 AN XY: 724886

Gnomad4 AFR exome AF: 0.0225

Gnomad4 AMR exome AF: 0.262

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.145

Gnomad4 SAS exome AF: 0.161

Gnomad4 FIN exome AF: 0.0729

Gnomad4 NFE exome AF: 0.142

Gnomad4 OTH exome AF: 0.134

GnomAD4 genome AF: 0.107 AC: 16359 AN: 152244 Hom.: 1177 Cov.: 33 AF XY: 0.108 AC XY: 8030 AN XY: 74444

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.197

Gnomad4 ASJ AF: 0.118

Gnomad4 EAS AF: 0.156

Gnomad4 SAS AF: 0.155

Gnomad4 FIN AF: 0.0737

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.114

Alfa AF: 0.119 Hom.: 301

Bravo AF: 0.116

Asia WGS AF: 0.162 AC: 565 AN: 3478

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

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	-0.92
Cadd	Benign	3.4
Dann	Benign	0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs10870199; hg19: chr9-139328551; COSMIC: COSV65496262; COSMIC: COSV65496262;