rs140797474

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_019892.6(INPP5E):c.1159+26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,608,534 control chromosomes in the GnomAD database, including 498 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 40 hom., cov: 34)

Exomes 𝑓: 0.021 ( 458 hom. )

Consequence

INPP5E
NM_019892.6 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.47

Publications

1 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.01).

BP6

Variant 9-136433129-G-A is Benign according to our data. Variant chr9-136433129-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6 link	c.1159+26C>T		intron_variant	Intron 4 of 9	ENST00000371712.4	NP_063945.2	Q9NRR6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712.4 link	c.1159+26C>T		intron_variant	Intron 4 of 9	1	NM_019892.6	ENSP00000360777.3		Q9NRR6-1
INPP5E	ENST00000676019.1 link	c.1057+26C>T		intron_variant	Intron 4 of 9			ENSP00000501984.1		Q9NRR6-2

Frequencies

GnomAD3 genomes

AF:

0.0164

AC:

2485

AN:

151474

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00524

Gnomad AMI

AF:

0.0287

Gnomad AMR

AF:

0.0245

Gnomad ASJ

AF:

0.0810

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00684

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.0414

Gnomad NFE

AF:

0.0215

Gnomad OTH

AF:

0.0274

GnomAD2 exomes

AF:

0.0184

AC:

4496

AN:

244508

AF XY:

0.0189

show subpopulations

Gnomad AFR exome

AF:

0.00568

Gnomad AMR exome

AF:

0.0172

Gnomad ASJ exome

AF:

0.0800

Gnomad EAS exome

AF:

0.000605

Gnomad FIN exome

AF:

0.00307

Gnomad NFE exome

AF:

0.0228

Gnomad OTH exome

AF:

0.0281

GnomAD4 exome

AF:

0.0212

AC:

30908

AN:

1456942

Hom.:

458

Cov.:

AF XY:

0.0212

AC XY:

15387

AN XY:

724940

show subpopulations

African (AFR)

AF:

0.00545

AC:

182

AN:

33410

American (AMR)

AF:

0.0179

AC:

802

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0801

AC:

2091

AN:

26108

East Asian (EAS)

AF:

0.000227

AC:

AN:

39664

South Asian (SAS)

AF:

0.00827

AC:

713

AN:

86234

European-Finnish (FIN)

AF:

0.00379

AC:

189

AN:

49888

Middle Eastern (MID)

AF:

0.0607

AC:

350

AN:

5768

European-Non Finnish (NFE)

AF:

0.0226

AC:

25083

AN:

1110912

Other (OTH)

AF:

0.0247

AC:

1489

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

1705

3411

5116

6822

8527

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

964

1928

2892

3856

4820

<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:

0.0164

AC:

2484

AN:

151592

Hom.:

Cov.:

AF XY:

0.0162

AC XY:

1200

AN XY:

74130

show subpopulations

African (AFR)

AF:

0.00522

AC:

215

AN:

41164

American (AMR)

AF:

0.0245

AC:

374

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0810

AC:

281

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00685

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00292

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0411

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0215

AC:

1455

AN:

67814

Other (OTH)

AF:

0.0271

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

124

247

371

494

618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0296

Hom.:

Bravo

AF:

0.0212

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 05, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.028

(source)

DANN

Benign

0.69

PhyloP100

-3.5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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