rs181576122

chr9-136431131-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_019892.6(INPP5E):c.1550-14C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,575,526 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (16 hom.)
• Consequence: INPP5E NM_019892.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.336

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=-0.84).
• BP6: Variant 9-136431131-G-A is Benign according to our data. Variant chr9-136431131-G-A is described in ClinVar as [Benign]. Clinvar id is 261199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00124 (187/151408) while in subpopulation AMR AF= 0.00808 (122/15106). AF 95% confidence interval is 0.00691. There are 2 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6	c.1550-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000371712.4
INPP5E	NM_001318502.2	c.1547-14C>T		splice_polypyrimidine_tract_variant, intron_variant
INPP5E	XM_017014926.2	c.1550-14C>T		splice_polypyrimidine_tract_variant, intron_variant
INPP5E	XM_047423603.1	c.1547-14C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5E	ENST00000371712.4	c.1550-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_019892.6	P1
INPP5E	ENST00000676019.1	c.1448-14C>T		splice_polypyrimidine_tract_variant, intron_variant
INPP5E	ENST00000674693.1	n.53C>T		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 184 AN: 151292 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00789

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00248

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00360 AC: 890 AN: 247214 Hom.: 10 AF XY: 0.00294 AC XY: 395 AN XY: 134170

Gnomad AFR exome AF: 0.000441

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000985

Gnomad SAS exome AF: 0.00168

Gnomad FIN exome AF: 0.00362

Gnomad NFE exome AF: 0.000171

Gnomad OTH exome AF: 0.00431

GnomAD4 exome AF: 0.00100 AC: 1429 AN: 1424118 Hom.: 16 Cov.: 25 AF XY: 0.000919 AC XY: 653 AN XY: 710630

Gnomad4 AFR exome AF: 0.000245

Gnomad4 AMR exome AF: 0.0184

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00188

Gnomad4 SAS exome AF: 0.00131

Gnomad4 FIN exome AF: 0.00290

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.00173

GnomAD4 genome AF: 0.00124 AC: 187 AN: 151408 Hom.: 2 Cov.: 31 AF XY: 0.00149 AC XY: 110 AN XY: 73946

Gnomad4 AFR AF: 0.000267

Gnomad4 AMR AF: 0.00808

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00117

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00248

Gnomad4 NFE AF: 0.000192

Gnomad4 OTH AF: 0.00238

Alfa AF: 0.00100 Hom.: 0

Bravo AF: 0.00295

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 04, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

INPP5E-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Joubert syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial aplasia of the vermis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	10
Dann	Benign	0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs181576122; hg19: chr9-139325583;