9-136428749-A-G

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.*926T>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 0.113 in 152,640 control chromosomes in the GnomAD database, including 1,179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1175 hom., cov: 32)
  • Exomes 𝑓: 0.099 (4 hom.)
• Consequence: INPP5E NM_019892.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.227

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=-0.89).
• BP6: Variant 9-136428749-A-G is Benign according to our data. Variant chr9-136428749-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 365866.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6	c.*926T>C		3_prime_UTR_variant	10/10	ENST00000371712.4
INPP5E	NM_001318502.2	c.*926T>C		3_prime_UTR_variant	10/10
INPP5E	XM_017014926.2	c.*1005T>C		3_prime_UTR_variant	10/10
INPP5E	XM_047423603.1	c.*1005T>C		3_prime_UTR_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5E	ENST00000371712.4	c.*926T>C		3_prime_UTR_variant	10/10	1	NM_019892.6	P1
INPP5E	ENST00000676019.1	c.*926T>C		3_prime_UTR_variant	10/10

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17169 AN: 152118 Hom.: 1167 Cov.: 32

Gnomad AFR AF: 0.0544

Gnomad AMI AF: 0.0749

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.0728

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.115

GnomAD4 exome AF: 0.0990 AC: 40 AN: 404 Hom.: 4 Cov.: 0 AF XY: 0.107 AC XY: 24 AN XY: 224

Gnomad4 EAS exome AF: 0.157

Gnomad4 FIN exome AF: 0.0714

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.113 AC: 17203 AN: 152236 Hom.: 1175 Cov.: 32 AF XY: 0.113 AC XY: 8401 AN XY: 74430

Gnomad4 AFR AF: 0.0548

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.0728

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.115

Alfa AF: 0.133 Hom.: 1865

Bravo AF: 0.122

Asia WGS AF: 0.158 AC: 550 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.89
Cadd	Benign	2.5
Dann	Benign	0.63

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: rs1128877; hg19: chr9-139323201; COSMIC: COSV65496941; COSMIC: COSV65496941;