9-136432582-A-G

Variant names:

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.1284T>C(p.Gly428Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,540,556 control chromosomes in the GnomAD database, including 151,687 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 13778 hom., cov: 32)

Exomes 𝑓: 0.44 ( 137909 hom. )

Consequence

INPP5E
NM_019892.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.92

Publications

40 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=-0.83).

BP6

Variant 9-136432582-A-G is Benign according to our data. Variant chr9-136432582-A-G is described in ClinVar as Benign. ClinVar VariationId is 129266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.92 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019892.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	NM_019892.6	MANE Select	c.1284T>C	p.Gly428Gly	synonymous	Exon 6 of 10	NP_063945.2
	INPP5E	NM_001318502.2		c.1281T>C	p.Cys427Cys	splice_region synonymous	Exon 6 of 10	NP_001305431.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	ENST00000371712.4	TSL:1 MANE Select	c.1284T>C	p.Gly428Gly	synonymous	Exon 6 of 10	ENSP00000360777.3
	INPP5E	ENST00000676019.1		c.1182T>C	p.Gly394Gly	synonymous	Exon 6 of 10	ENSP00000501984.1

Frequencies

GnomAD3 genomes

AF:

0.421

AC:

63907

AN:

151890

Hom.:

13748

Cov.:

show subpopulations

Gnomad AFR

AF:

0.399

Gnomad AMI

AF:

0.391

Gnomad AMR

AF:

0.527

Gnomad ASJ

AF:

0.451

Gnomad EAS

AF:

0.207

Gnomad SAS

AF:

0.327

Gnomad FIN

AF:

0.326

Gnomad MID

AF:

0.414

Gnomad NFE

AF:

0.446

Gnomad OTH

AF:

0.439

GnomAD2 exomes

AF:

0.421

AC:

65329

AN:

155342

AF XY:

0.409

show subpopulations

Gnomad AFR exome

AF:

0.395

Gnomad AMR exome

AF:

0.566

Gnomad ASJ exome

AF:

0.439

Gnomad EAS exome

AF:

0.194

Gnomad FIN exome

AF:

0.334

Gnomad NFE exome

AF:

0.456

Gnomad OTH exome

AF:

0.434

GnomAD4 exome

AF:

0.441

AC:

611967

AN:

1388546

Hom.:

137909

Cov.:

AF XY:

0.437

AC XY:

299396

AN XY:

685382

show subpopulations

African (AFR)

AF:

0.395

AC:

12410

AN:

31412

American (AMR)

AF:

0.566

AC:

20207

AN:

35694

Ashkenazi Jewish (ASJ)

AF:

0.443

AC:

11123

AN:

25118

East Asian (EAS)

AF:

0.226

AC:

8090

AN:

35798

South Asian (SAS)

AF:

0.334

AC:

26450

AN:

79082

European-Finnish (FIN)

AF:

0.336

AC:

15866

AN:

47206

Middle Eastern (MID)

AF:

0.384

AC:

2178

AN:

5674

European-Non Finnish (NFE)

AF:

0.458

AC:

490953

AN:

1070890

Other (OTH)

AF:

0.428

AC:

24690

AN:

57672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

17351

34702

52054

69405

86756

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14814

29628

44442

59256

74070

<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:

0.421

AC:

63986

AN:

152010

Hom.:

13778

Cov.:

AF XY:

0.414

AC XY:

30795

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.400

AC:

16578

AN:

41466

American (AMR)

AF:

0.528

AC:

8064

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.451

AC:

1561

AN:

3464

East Asian (EAS)

AF:

0.206

AC:

1064

AN:

5156

South Asian (SAS)

AF:

0.327

AC:

1574

AN:

4816

European-Finnish (FIN)

AF:

0.326

AC:

3444

AN:

10566

Middle Eastern (MID)

AF:

0.422

AC:

124

AN:

294

European-Non Finnish (NFE)

AF:

0.446

AC:

30295

AN:

67946

Other (OTH)

AF:

0.439

AC:

926

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1908

3817

5725

7634

9542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

590

1180

1770

2360

2950

<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:

0.445

Hom.:

23557

Bravo

AF:

0.436

Asia WGS

AF:

0.320

AC:

1112

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Joubert syndrome 1 (2)

not provided (2)

Joubert syndrome (1)

MORM syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.13

(source)

DANN

Benign

0.36

PhyloP100

-2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over