rs144347039

chr9-136433125-A-T

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+30T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0209 in 1,609,640 control chromosomes in the GnomAD database, including 501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (40 hom., cov: 34)
  • Exomes 𝑓: 0.021 (461 hom.)
• Consequence: INPP5E NM_019892.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.57

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 9-136433125-A-T is Benign according to our data. Variant chr9-136433125-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 261189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6	c.1159+30T>A		intron_variant		ENST00000371712.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5E	ENST00000371712.4	c.1159+30T>A		intron_variant		1	NM_019892.6	P1
INPP5E	ENST00000676019.1	c.1057+30T>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2569 AN: 151564 Hom.: 40 Cov.: 34

Gnomad AFR AF: 0.00714

Gnomad AMI AF: 0.0285

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: 0.0478

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0279

GnomAD3 exomes AF: 0.0185 AC: 4537 AN: 245098 Hom.: 75 AF XY: 0.0190 AC XY: 2544 AN XY: 133560

Gnomad AFR exome AF: 0.00766

Gnomad AMR exome AF: 0.0171

Gnomad ASJ exome AF: 0.0800

Gnomad EAS exome AF: 0.000659

Gnomad SAS exome AF: 0.00807

Gnomad FIN exome AF: 0.00302

Gnomad NFE exome AF: 0.0228

Gnomad OTH exome AF: 0.0285

GnomAD4 exome AF: 0.0213 AC: 31058 AN: 1457958 Hom.: 461 Cov.: 54 AF XY: 0.0213 AC XY: 15474 AN XY: 725400

Gnomad4 AFR exome AF: 0.00743

Gnomad4 AMR exome AF: 0.0178

Gnomad4 ASJ exome AF: 0.0801

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00822

Gnomad4 FIN exome AF: 0.00377

Gnomad4 NFE exome AF: 0.0226

Gnomad4 OTH exome AF: 0.0247

GnomAD4 genome AF: 0.0169 AC: 2567 AN: 151682 Hom.: 40 Cov.: 34 AF XY: 0.0167 AC XY: 1237 AN XY: 74166

Gnomad4 AFR AF: 0.00712

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: 0.0276

Alfa AF: 0.0297 Hom.: 14

Bravo AF: 0.0218

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	0.95
Dann	Benign	0.38

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: rs144347039; hg19: chr9-139327577;