rs74880446

chr9-136431867-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_019892.6(INPP5E):c.1506G>A(p.Pro502=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,609,570 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: INPP5E NM_019892.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.0160

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 9-136431867-C-T is Benign according to our data. Variant chr9-136431867-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 365880.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr9-136431867-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.016 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00104 (156/149496) while in subpopulation NFE AF= 0.00193 (130/67370). AF 95% confidence interval is 0.00166. There are 0 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5E	NM_019892.6	c.1506G>A	p.Pro502=	synonymous_variant	7/10	ENST00000371712.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5E	ENST00000371712.4	c.1506G>A	p.Pro502=	synonymous_variant	7/10	1	NM_019892.6	P1
INPP5E	ENST00000676019.1	c.1404G>A	p.Pro468=	synonymous_variant	7/10

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 156 AN: 149378 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000669

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000656

Gnomad FIN AF: 0.000673

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.000992

GnomAD3 exomes AF: 0.000861 AC: 212 AN: 246178 Hom.: 0 AF XY: 0.00101 AC XY: 135 AN XY: 134188

Gnomad AFR exome AF: 0.000316

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000705

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.000491

Gnomad FIN exome AF: 0.000934

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.000829

GnomAD4 exome AF: 0.00117 AC: 1709 AN: 1460074 Hom.: 2 Cov.: 36 AF XY: 0.00119 AC XY: 866 AN XY: 726382

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.000843

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.00106

Gnomad4 NFE exome AF: 0.00136

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.00104 AC: 156 AN: 149496 Hom.: 0 Cov.: 29 AF XY: 0.00108 AC XY: 79 AN XY: 72890

Gnomad4 AFR AF: 0.000198

Gnomad4 AMR AF: 0.0000668

Gnomad4 ASJ AF: 0.00145

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000656

Gnomad4 FIN AF: 0.000673

Gnomad4 NFE AF: 0.00193

Gnomad4 OTH AF: 0.000981

Alfa AF: 0.00169 Hom.: 0

Bravo AF: 0.000869

EpiCase AF: 0.00153

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	INPP5E: BP4, BP7 -

Joubert syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Familial aplasia of the vermis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.58
Dann	Benign	0.64

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: rs74880446; hg19: chr9-139326319;