rs34302850

Positions:

• chr9-136432612-A-G

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.1280-26T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,418,354 control chromosomes in the GnomAD database, including 57,931 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.25 (5217 hom., cov: 33)
  • Exomes 𝑓: 0.28 (52714 hom.)
• Consequence: INPP5E NM_019892.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.72

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: This place is a probable branch point but likely benign (scored 0 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-136432612-A-G is Benign according to our data. Variant chr9-136432612-A-G is described in ClinVar as [Benign]. Clinvar id is 261192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6	c.1280-26T>C		intron_variant		ENST00000371712.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5E	ENST00000371712.4	c.1280-26T>C		intron_variant		1	NM_019892.6	P1
INPP5E	ENST00000676019.1	c.1178-26T>C		intron_variant

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38630 AN: 151922 Hom.: 5216 Cov.: 33

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.0557

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.275

GnomAD3 exomes AF: 0.256 AC: 39039 AN: 152248 Hom.: 5617 AF XY: 0.250 AC XY: 20161 AN XY: 80488

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.291

Gnomad ASJ exome AF: 0.323

Gnomad EAS exome AF: 0.0424

Gnomad SAS exome AF: 0.172

Gnomad FIN exome AF: 0.271

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.282 AC: 356609 AN: 1266314 Hom.: 52714 Cov.: 19 AF XY: 0.278 AC XY: 175651 AN XY: 630720

Gnomad4 AFR exome AF: 0.176

Gnomad4 AMR exome AF: 0.291

Gnomad4 ASJ exome AF: 0.323

Gnomad4 EAS exome AF: 0.0888

Gnomad4 SAS exome AF: 0.170

Gnomad4 FIN exome AF: 0.263

Gnomad4 NFE exome AF: 0.301

Gnomad4 OTH exome AF: 0.271

GnomAD4 genome AF: 0.254 AC: 38649 AN: 152040 Hom.: 5217 Cov.: 33 AF XY: 0.250 AC XY: 18613 AN XY: 74338

Gnomad4 AFR AF: 0.183

Gnomad4 AMR AF: 0.298

Gnomad4 ASJ AF: 0.321

Gnomad4 EAS AF: 0.0552

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.251

Gnomad4 NFE AF: 0.305

Gnomad4 OTH AF: 0.276

Alfa AF: 0.291 Hom.: 1803

Bravo AF: 0.253

Asia WGS AF: 0.147 AC: 511 AN: 3476

ClinVar

Significance: 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.31
BranchPoint Hunter		0.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs34302850; hg19: chr9-139327064;