9-136433147-G-GCGCCCACCCCTCCAGCCA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_019892.6(INPP5E):c.1159+7_1159+8insTGGCTGGAGGGGTGGGCG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 147,718 control chromosomes in the GnomAD database, including 5,144 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5144 hom., cov: 28)

Exomes 𝑓: 0.29 ( 63852 hom. )

Failed GnomAD Quality Control

Consequence

INPP5E
NM_019892.6 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.695

Publications

8 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 -16 ACMG points.

BP6

Variant 9-136433147-G-GCGCCCACCCCTCCAGCCA is Benign according to our data. Variant chr9-136433147-G-GCGCCCACCCCTCCAGCCA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6 link	c.1159+7_1159+8insTGGCTGGAGGGGTGGGCG		splice_region_variant, 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+7_1159+8insTGGCTGGAGGGGTGGGCG		splice_region_variant, intron_variant	Intron 4 of 9	1	NM_019892.6	ENSP00000360777.3		Q9NRR6-1
INPP5E	ENST00000676019.1 link	c.1057+7_1057+8insTGGCTGGAGGGGTGGGCG		splice_region_variant, intron_variant	Intron 4 of 9			ENSP00000501984.1		Q9NRR6-2

Frequencies

GnomAD3 genomes

AF:

0.258

AC:

38034

AN:

147600

Hom.:

5142

Cov.:

show subpopulations

Gnomad AFR

AF:

0.196

Gnomad AMI

AF:

0.287

Gnomad AMR

AF:

0.286

Gnomad ASJ

AF:

0.247

Gnomad EAS

AF:

0.0447

Gnomad SAS

AF:

0.164

Gnomad FIN

AF:

0.277

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.307

Gnomad OTH

AF:

0.263

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.289

AC:

417440

AN:

1443622

Hom.:

63852

Cov.:

AF XY:

0.285

AC XY:

204963

AN XY:

718522

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.187

AC:

6224

AN:

33230

American (AMR)

AF:

0.283

AC:

12533

AN:

44356

Ashkenazi Jewish (ASJ)

AF:

0.253

AC:

6558

AN:

25930

East Asian (EAS)

AF:

0.0762

AC:

3014

AN:

39548

South Asian (SAS)

AF:

0.170

AC:

14655

AN:

86004

European-Finnish (FIN)

AF:

0.276

AC:

12748

AN:

46118

Middle Eastern (MID)

AF:

0.187

AC:

1069

AN:

5720

European-Non Finnish (NFE)

AF:

0.313

AC:

344694

AN:

1102892

Other (OTH)

AF:

0.267

AC:

15945

AN:

59824

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.377

Heterozygous variant carriers

15331

30662

45992

61323

76654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10980

21960

32940

43920

54900

<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:

0.258

AC:

38065

AN:

147718

Hom.:

5144

Cov.:

AF XY:

0.252

AC XY:

18158

AN XY:

72098

show subpopulations

African (AFR)

AF:

0.196

AC:

7587

AN:

38758

American (AMR)

AF:

0.286

AC:

4242

AN:

14840

Ashkenazi Jewish (ASJ)

AF:

0.247

AC:

854

AN:

3454

East Asian (EAS)

AF:

0.0446

AC:

229

AN:

5134

South Asian (SAS)

AF:

0.163

AC:

778

AN:

4762

European-Finnish (FIN)

AF:

0.277

AC:

2838

AN:

10250

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.307

AC:

20677

AN:

67270

Other (OTH)

AF:

0.263

AC:

541

AN:

2054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

1231

2463

3694

4926

6157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

384

768

1152

1536

1920

<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:

0.209

Hom.:

959

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 24, 2022

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joubert syndrome

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.69

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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