rs33982662

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_019892.6(INPP5E):c.1794G>T(p.Gly598Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,551,170 control chromosomes in the GnomAD database, including 55,551 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4198 hom., cov: 33)

Exomes 𝑓: 0.27 ( 51353 hom. )

Consequence

INPP5E
NM_019892.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.20

Publications

25 publications found

Variant links:

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]

INPP5E Gene-Disease associations (from GenCC):

Joubert syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
MORM syndrome
Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, ClinGen, Orphanet
COACH syndrome 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome with ocular defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

INPP5E links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 9-136430285-C-A is Benign according to our data. Variant chr9-136430285-C-A is described in ClinVar as Benign. ClinVar VariationId is 129272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.2 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6 link	c.1794G>T	p.Gly598Gly	synonymous_variant	Exon 9 of 10	ENST00000371712.4	NP_063945.2	Q9NRR6-1
INPP5E	NM_001318502.2 link	c.1791G>T	p.Gly597Gly	synonymous_variant	Exon 9 of 10		NP_001305431.1	Q9NRR6
INPP5E	XM_017014926.2 link	c.1794G>T	p.Gly598Gly	synonymous_variant	Exon 9 of 10		XP_016870415.1
INPP5E	XM_047423603.1 link	c.1791G>T	p.Gly597Gly	synonymous_variant	Exon 9 of 10		XP_047279559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INPP5E	ENST00000371712.4 link	c.1794G>T	p.Gly598Gly	synonymous_variant	Exon 9 of 10	1	NM_019892.6	ENSP00000360777.3	Q9NRR6-1
INPP5E	ENST00000676019.1 link	c.1692G>T	p.Gly564Gly	synonymous_variant	Exon 9 of 10			ENSP00000501984.1	Q9NRR6-2
INPP5E	ENST00000674693.1 link	n.*50G>T		downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.226

AC:

34349

AN:

152082

Hom.:

4198

Cov.:

show subpopulations

Gnomad AFR

AF:

0.148

Gnomad AMI

AF:

0.285

Gnomad AMR

AF:

0.258

Gnomad ASJ

AF:

0.214

Gnomad EAS

AF:

0.0510

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.249

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.280

Gnomad OTH

AF:

0.224

GnomAD2 exomes

AF:

0.231

AC:

36057

AN:

156394

AF XY:

0.225

show subpopulations

Gnomad AFR exome

AF:

0.148

Gnomad AMR exome

AF:

0.266

Gnomad ASJ exome

AF:

0.216

Gnomad EAS exome

AF:

0.0342

Gnomad FIN exome

AF:

0.260

Gnomad NFE exome

AF:

0.284

Gnomad OTH exome

AF:

0.241

GnomAD4 exome

AF:

0.265

AC:

371011

AN:

1398970

Hom.:

51353

Cov.:

AF XY:

0.262

AC XY:

180633

AN XY:

690020

show subpopulations

African (AFR)

AF:

0.145

AC:

4597

AN:

31602

American (AMR)

AF:

0.263

AC:

9405

AN:

35696

Ashkenazi Jewish (ASJ)

AF:

0.219

AC:

5513

AN:

25178

East Asian (EAS)

AF:

0.0839

AC:

2998

AN:

35744

South Asian (SAS)

AF:

0.163

AC:

12886

AN:

79236

European-Finnish (FIN)

AF:

0.258

AC:

12616

AN:

48862

Middle Eastern (MID)

AF:

0.162

AC:

922

AN:

5696

European-Non Finnish (NFE)

AF:

0.286

AC:

308134

AN:

1078948

Other (OTH)

AF:

0.240

AC:

13940

AN:

58008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

15923

31846

47768

63691

79614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10206

20412

30618

40824

51030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.226

AC:

34362

AN:

152200

Hom.:

4198

Cov.:

AF XY:

0.222

AC XY:

16521

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.148

AC:

6151

AN:

41530

American (AMR)

AF:

0.258

AC:

3947

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.214

AC:

742

AN:

3470

East Asian (EAS)

AF:

0.0508

AC:

263

AN:

5180

South Asian (SAS)

AF:

0.161

AC:

778

AN:

4830

European-Finnish (FIN)

AF:

0.249

AC:

2638

AN:

10604

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.280

AC:

19057

AN:

67972

Other (OTH)

AF:

0.225

AC:

475

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1356

2711

4067

5422

6778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.239

Hom.:

3050

Bravo

AF:

0.220

Asia WGS

AF:

0.132

AC:

457

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joubert syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joubert syndrome 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.98

(source)

DANN

Benign

0.82

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over