rs140797474

chr9-136433129-G-Achr9-136433129-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019892.6(INPP5E):c.1159+26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,608,534 control chromosomes in the GnomAD database, including 498 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (40 hom., cov: 34)
  • Exomes 𝑓: 0.021 (458 hom.)
• Consequence: INPP5E NM_019892.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.47

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 9-136433129-G-A is Benign according to our data. Variant chr9-136433129-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6	c.1159+26C>T		intron_variant		ENST00000371712.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5E	ENST00000371712.4	c.1159+26C>T		intron_variant		1	NM_019892.6	P1
INPP5E	ENST00000676019.1	c.1057+26C>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2485 AN: 151474 Hom.: 40 Cov.: 34

Gnomad AFR AF: 0.00524

Gnomad AMI AF: 0.0287

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.0810

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00684

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0274

GnomAD3 exomes AF: 0.0184 AC: 4496 AN: 244508 Hom.: 74 AF XY: 0.0189 AC XY: 2521 AN XY: 133290

Gnomad AFR exome AF: 0.00568

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.0800

Gnomad EAS exome AF: 0.000605

Gnomad SAS exome AF: 0.00805

Gnomad FIN exome AF: 0.00307

Gnomad NFE exome AF: 0.0228

Gnomad OTH exome AF: 0.0281

GnomAD4 exome AF: 0.0212 AC: 30908 AN: 1456942 Hom.: 458 Cov.: 55 AF XY: 0.0212 AC XY: 15387 AN XY: 724940

Gnomad4 AFR exome AF: 0.00545

Gnomad4 AMR exome AF: 0.0179

Gnomad4 ASJ exome AF: 0.0801

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00827

Gnomad4 FIN exome AF: 0.00379

Gnomad4 NFE exome AF: 0.0226

Gnomad4 OTH exome AF: 0.0247

GnomAD4 genome AF: 0.0164 AC: 2484 AN: 151592 Hom.: 40 Cov.: 34 AF XY: 0.0162 AC XY: 1200 AN XY: 74130

Gnomad4 AFR AF: 0.00522

Gnomad4 AMR AF: 0.0245

Gnomad4 ASJ AF: 0.0810

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00685

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.0215

Gnomad4 OTH AF: 0.0271

Alfa AF: 0.0296 Hom.: 14

Bravo AF: 0.0212

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.028
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs140797474; hg19: chr9-139327581;