9-136428859-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_019892.6(INPP5E):c.*816A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 152,382 control chromosomes in the GnomAD database, including 12,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (12228 hom., cov: 32)
  • Exomes 𝑓: 0.33 (21 hom.)
• Consequence: INPP5E NM_019892.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.21

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-136428859-T-C is Benign according to our data. Variant chr9-136428859-T-C is described in ClinVar as [Benign]. Clinvar id is 365868.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6	c.*816A>G		3_prime_UTR_variant	10/10	ENST00000371712.4
INPP5E	NM_001318502.2	c.*816A>G		3_prime_UTR_variant	10/10
INPP5E	XM_017014926.2	c.*895A>G		3_prime_UTR_variant	10/10
INPP5E	XM_047423603.1	c.*895A>G		3_prime_UTR_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5E	ENST00000371712.4	c.*816A>G		3_prime_UTR_variant	10/10	1	NM_019892.6	P1
INPP5E	ENST00000676019.1	c.*816A>G		3_prime_UTR_variant	10/10

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60240 AN: 151968 Hom.: 12199 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.395

GnomAD4 exome AF: 0.328 AC: 97 AN: 296 Hom.: 21 Cov.: 0 AF XY: 0.317 AC XY: 45 AN XY: 142

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.438

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.256

Gnomad4 NFE exome AF: 0.256

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.397 AC: 60318 AN: 152086 Hom.: 12228 Cov.: 32 AF XY: 0.390 AC XY: 29028 AN XY: 74336

Gnomad4 AFR AF: 0.379

Gnomad4 AMR AF: 0.493

Gnomad4 ASJ AF: 0.338

Gnomad4 EAS AF: 0.206

Gnomad4 SAS AF: 0.320

Gnomad4 FIN AF: 0.322

Gnomad4 NFE AF: 0.421

Gnomad4 OTH AF: 0.395

Alfa AF: 0.412 Hom.: 19874

Bravo AF: 0.407

Asia WGS AF: 0.310 AC: 1079 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 1 Benign:1

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.88
Dann	Benign	0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs8413; hg19: chr9-139323311; COSMIC: COSV65496226;