9-136429347-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.*328T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 437,152 control chromosomes in the GnomAD database, including 40,394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14191 hom., cov: 32)
  • Exomes 𝑓: 0.42 (26203 hom.)
• Consequence: INPP5E NM_019892.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.405

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=-0.95).
• BP6: Variant 9-136429347-A-G is Benign according to our data. Variant chr9-136429347-A-G is described in ClinVar as [Benign]. Clinvar id is 365875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6	c.*328T>C		3_prime_UTR_variant	10/10	ENST00000371712.4
INPP5E	NM_001318502.2	c.*328T>C		3_prime_UTR_variant	10/10
INPP5E	XM_017014926.2	c.*407T>C		3_prime_UTR_variant	10/10
INPP5E	XM_047423603.1	c.*407T>C		3_prime_UTR_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5E	ENST00000371712.4	c.*328T>C		3_prime_UTR_variant	10/10	1	NM_019892.6	P1
INPP5E	ENST00000676019.1	c.*328T>C		3_prime_UTR_variant	10/10

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64828 AN: 151856 Hom.: 14160 Cov.: 32

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.448

GnomAD4 exome AF: 0.418 AC: 119262 AN: 285178 Hom.: 26203 Cov.: 0 AF XY: 0.409 AC XY: 62421 AN XY: 152740

Gnomad4 AFR exome AF: 0.417

Gnomad4 AMR exome AF: 0.555

Gnomad4 ASJ exome AF: 0.452

Gnomad4 EAS exome AF: 0.213

Gnomad4 SAS exome AF: 0.332

Gnomad4 FIN exome AF: 0.337

Gnomad4 NFE exome AF: 0.453

Gnomad4 OTH exome AF: 0.431

GnomAD4 genome AF: 0.427 AC: 64910 AN: 151974 Hom.: 14191 Cov.: 32 AF XY: 0.421 AC XY: 31239 AN XY: 74268

Gnomad4 AFR AF: 0.418

Gnomad4 AMR AF: 0.532

Gnomad4 ASJ AF: 0.450

Gnomad4 EAS AF: 0.206

Gnomad4 SAS AF: 0.327

Gnomad4 FIN AF: 0.327

Gnomad4 NFE AF: 0.447

Gnomad4 OTH AF: 0.447

Alfa AF: 0.370 Hom.: 1719

Bravo AF: 0.442

Asia WGS AF: 0.316 AC: 1100 AN: 3478

ClinVar

Significance: 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 14, 2018

- -

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	-0.95
Cadd	Benign	1.9
Dann	Benign	0.31

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: rs35763810; hg19: chr9-139323799;