9-136428972-T-C

Variant names:

• chr9-136428972-T-C
• rs1128874
• NM_019892.6:c.*703A>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.*703A>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 0.42 in 152,310 control chromosomes in the GnomAD database, including 13,715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13619 hom., cov: 32)
  • Exomes 𝑓: 0.38 (96 hom.)
• Consequence: INPP5E NM_019892.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.68

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=-0.91).
• BP6: Variant 9-136428972-T-C is Benign according to our data. Variant chr9-136428972-T-C is described in ClinVar as [Benign]. Clinvar id is 365873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6	c.*703A>G		3_prime_UTR_variant	Exon 10 of 10	ENST00000371712.4	NP_063945.2
INPP5E	NM_001318502.2	c.*703A>G		3_prime_UTR_variant	Exon 10 of 10		NP_001305431.1
INPP5E	XM_017014926.2	c.*782A>G		3_prime_UTR_variant	Exon 10 of 10		XP_016870415.1
INPP5E	XM_047423603.1	c.*782A>G		3_prime_UTR_variant	Exon 10 of 10		XP_047279559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712	c.*703A>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_019892.6	ENSP00000360777.3
INPP5E	ENST00000676019	c.*703A>G		3_prime_UTR_variant	Exon 10 of 10			ENSP00000501984.1

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63467 AN: 151150 Hom.: 13589 Cov.: 32

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.440

GnomAD4 exome AF: 0.378 AC: 395 AN: 1046 Hom.: 96 Cov.: 0 AF XY: 0.391 AC XY: 214 AN XY: 548

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.552

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.415

Gnomad4 SAS exome AF: 0.319

Gnomad4 FIN exome AF: 0.100

Gnomad4 NFE exome AF: 0.351

Gnomad4 OTH exome AF: 0.239

GnomAD4 genome AF: 0.420 AC: 63543 AN: 151264 Hom.: 13619 Cov.: 32 AF XY: 0.414 AC XY: 30596 AN XY: 73978

Gnomad4 AFR AF: 0.394

Gnomad4 AMR AF: 0.526

Gnomad4 ASJ AF: 0.450

Gnomad4 EAS AF: 0.204

Gnomad4 SAS AF: 0.328

Gnomad4 FIN AF: 0.326

Gnomad4 NFE AF: 0.448

Gnomad4 OTH AF: 0.440

Alfa AF: 0.456 Hom.: 3836

Bravo AF: 0.435

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Joubert syndrome 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	1.3
DANN	Benign	0.28

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: rs1128874; hg19: chr9-139323424;