9-136433146-C-CGCGCCCACCCCTCCAGCT

Variant names:

• chr9-136433146-C-CGCGCCCACCCCTCCAGCT
• rs747240016
• NM_019892.6:c.1159+8_1159+9insAGCTGGAGGGGTGGGCGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_019892.6(INPP5E):​c.1159+8_1159+9insAGCTGGAGGGGTGGGCGC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,608,090 control chromosomes in the GnomAD database, including 37 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (20 hom., cov: 30)
  • Exomes 𝑓: 0.00090 (17 hom.)
• Consequence: INPP5E NM_019892.6 splice_region, intron
• Clinical Significance: Likely 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.

• BP6: Variant 9-136433146-C-CGCGCCCACCCCTCCAGCT is Benign according to our data. Variant chr9-136433146-C-CGCGCCCACCCCTCCAGCT is described in ClinVar as [Likely_benign]. Clinvar id is 415748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00931 (1413/151724) while in subpopulation AFR AF= 0.0316 (1305/41348). AF 95% confidence interval is 0.0301. There are 20 homozygotes in gnomad4. There are 691 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6	c.1159+8_1159+9insAGCTGGAGGGGTGGGCGC		splice_region_variant, intron_variant	Intron 4 of 9	ENST00000371712.4	NP_063945.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712.4	c.1159+8_1159+9insAGCTGGAGGGGTGGGCGC		splice_region_variant, intron_variant	Intron 4 of 9	1	NM_019892.6	ENSP00000360777.3
INPP5E	ENST00000676019.1	c.1057+8_1057+9insAGCTGGAGGGGTGGGCGC		splice_region_variant, intron_variant	Intron 4 of 9			ENSP00000501984.1

Frequencies

GnomAD3 genomes AF: 0.00930 AC: 1410 AN: 151606 Hom.: 20 Cov.: 30

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00572

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.00823

GnomAD3 exomes AF: 0.00220 AC: 526 AN: 239056 Hom.: 6 AF XY: 0.00173 AC XY: 226 AN XY: 130476

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.00196

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000275

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.000899 AC: 1309 AN: 1456366 Hom.: 17 Cov.: 42 AF XY: 0.000776 AC XY: 562 AN XY: 724694

Gnomad4 AFR exome AF: 0.0321

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.00931 AC: 1413 AN: 151724 Hom.: 20 Cov.: 30 AF XY: 0.00932 AC XY: 691 AN XY: 74154

Gnomad4 AFR AF: 0.0316

Gnomad4 AMR AF: 0.00571

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000590

Gnomad4 OTH AF: 0.00814

Alfa AF: 0.00219 Hom.: 0

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2016	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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

Familial aplasia of the vermis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2025

- -

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: rs747240016; hg19: chr9-139327598;