rs73566945

chr9-136433147-G-Achr9-136433147-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_019892.6(INPP5E):c.1159+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,599,200 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0013 (6 hom.)
• Consequence: INPP5E NM_019892.6 splice_region, intron
• Scores: Splicing: ADA: 0.00007583
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.284

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-136433147-G-A is Benign according to our data. Variant chr9-136433147-G-A is described in ClinVar as [Benign]. Clinvar id is 129264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136433147-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00264 (391/148312) while in subpopulation AFR AF= 0.00516 (201/38928). AF 95% confidence interval is 0.00458. There are 1 homozygotes in gnomad4. There are 190 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6	c.1159+8C>T		splice_region_variant, intron_variant		ENST00000371712.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5E	ENST00000371712.4	c.1159+8C>T		splice_region_variant, intron_variant		1	NM_019892.6	P1
INPP5E	ENST00000676019.1	c.1057+8C>T		splice_region_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 391 AN: 148200 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00518

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.00167

Gnomad ASJ AF: 0.00203

Gnomad EAS AF: 0.00388

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00232

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.00246

GnomAD4 exome AF: 0.00132 AC: 1916 AN: 1450888 Hom.: 6 Cov.: 42 AF XY: 0.00131 AC XY: 947 AN XY: 722030

Gnomad4 AFR exome AF: 0.00417

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.000959

Gnomad4 EAS exome AF: 0.00303

Gnomad4 SAS exome AF: 0.000848

Gnomad4 FIN exome AF: 0.00667

Gnomad4 NFE exome AF: 0.000915

Gnomad4 OTH exome AF: 0.00168

GnomAD4 genome AF: 0.00264 AC: 391 AN: 148312 Hom.: 1 Cov.: 30 AF XY: 0.00262 AC XY: 190 AN XY: 72424

Gnomad4 AFR AF: 0.00516

Gnomad4 AMR AF: 0.00167

Gnomad4 ASJ AF: 0.00203

Gnomad4 EAS AF: 0.00389

Gnomad4 SAS AF: 0.00126

Gnomad4 FIN AF: 0.00232

Gnomad4 NFE AF: 0.00150

Gnomad4 OTH AF: 0.00243

Alfa AF: 0.129 Hom.: 11

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Joubert syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Familial aplasia of the vermis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.3
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000076
dbscSNV1_RF	Benign	0.0
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: rs73566945; hg19: chr9-139327599; COSMIC: COSV65496129; COSMIC: COSV65496129;