9-136433147-G-GCGCCCACCCCTCCAGCCA

Position:

• chr9-136433147-G-GCGCCCACCCCTCCAGCCA

Variant summary

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

The NM_019892.6(INPP5E):​c.1159+7_1159+8insTGGCTGGAGGGGTGGGCG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 147,718 control chromosomes in the GnomAD database, including 5,144 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5144 hom., cov: 28)
  • Exomes 𝑓: 0.29 (63852 hom.)
  • Failed GnomAD Quality Control
• Consequence: INPP5E NM_019892.6 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.695

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 9-136433147-G-GCGCCCACCCCTCCAGCCA is Benign according to our data. Variant chr9-136433147-G-GCGCCCACCCCTCCAGCCA is described in ClinVar as [Likely_benign]. Clinvar id is 215526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6	c.1159+7_1159+8insTGGCTGGAGGGGTGGGCG		splice_region_variant, intron_variant		ENST00000371712.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5E	ENST00000371712.4	c.1159+7_1159+8insTGGCTGGAGGGGTGGGCG		splice_region_variant, intron_variant		1	NM_019892.6	P1
INPP5E	ENST00000676019.1	c.1057+7_1057+8insTGGCTGGAGGGGTGGGCG		splice_region_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.258 AC: 38034 AN: 147600 Hom.: 5142 Cov.: 28

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.0447

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.263

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.289 AC: 417440 AN: 1443622 Hom.: 63852 Cov.: 53 AF XY: 0.285 AC XY: 204963 AN XY: 718522

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.283

Gnomad4 ASJ exome AF: 0.253

Gnomad4 EAS exome AF: 0.0762

Gnomad4 SAS exome AF: 0.170

Gnomad4 FIN exome AF: 0.276

Gnomad4 NFE exome AF: 0.313

Gnomad4 OTH exome AF: 0.267

GnomAD4 genome AF: 0.258 AC: 38065 AN: 147718 Hom.: 5144 Cov.: 28 AF XY: 0.252 AC XY: 18158 AN XY: 72098

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.286

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.0446

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.277

Gnomad4 NFE AF: 0.307

Gnomad4 OTH AF: 0.263

Alfa AF: 0.209 Hom.: 959

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 24, 2022	- -

not provided Benign:2

Likely 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	GeneDx	Mar 03, 2015	- -

Familial aplasia of the vermis Benign:2

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

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs71269007; hg19: chr9-139327599;