9-136429577-C-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.*98G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,510,922 control chromosomes in the GnomAD database, including 52,271 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3770 hom., cov: 32)
  • Exomes 𝑓: 0.26 (48501 hom.)
• Consequence: INPP5E NM_019892.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.846

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=-0.9).
• BP6: Variant 9-136429577-C-T is Benign according to our data. Variant chr9-136429577-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 365877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6	c.*98G>A		3_prime_UTR_variant	10/10	ENST00000371712.4
INPP5E	NM_001318502.2	c.*98G>A		3_prime_UTR_variant	10/10
INPP5E	XM_017014926.2	c.*177G>A		3_prime_UTR_variant	10/10
INPP5E	XM_047423603.1	c.*177G>A		3_prime_UTR_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5E	ENST00000371712.4	c.*98G>A		3_prime_UTR_variant	10/10	1	NM_019892.6	P1
INPP5E	ENST00000676019.1	c.*98G>A		3_prime_UTR_variant	10/10

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31146 AN: 152074 Hom.: 3770 Cov.: 32

Gnomad AFR AF: 0.0771

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.0513

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.209

GnomAD4 exome AF: 0.259 AC: 352103 AN: 1358730 Hom.: 48501 Cov.: 21 AF XY: 0.256 AC XY: 174396 AN XY: 681010

Gnomad4 AFR exome AF: 0.0670

Gnomad4 AMR exome AF: 0.260

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.0795

Gnomad4 SAS exome AF: 0.164

Gnomad4 FIN exome AF: 0.258

Gnomad4 NFE exome AF: 0.282

Gnomad4 OTH exome AF: 0.234

GnomAD4 genome AF: 0.205 AC: 31161 AN: 152192 Hom.: 3770 Cov.: 32 AF XY: 0.202 AC XY: 15019 AN XY: 74412

Gnomad4 AFR AF: 0.0771

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.214

Gnomad4 EAS AF: 0.0510

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.279

Gnomad4 OTH AF: 0.211

Alfa AF: 0.258 Hom.: 1081

Bravo AF: 0.196

Asia WGS AF: 0.128 AC: 446 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Joubert syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.59
Dann	Benign	0.56

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: rs35873563; hg19: chr9-139324029; COSMIC: COSV65497483;