9-136431852-G-A

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.1521C>T(p.His507His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,585,362 control chromosomes in the GnomAD database, including 15,661 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1067 hom., cov: 26)

Exomes 𝑓: 0.13 ( 14594 hom. )

Consequence

INPP5E
NM_019892.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.37

Publications

12 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=-0.89).

BP6

Variant 9-136431852-G-A is Benign according to our data. Variant chr9-136431852-G-A is described in ClinVar as Benign. ClinVar VariationId is 129268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.37 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.185 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.1521C>T	p.His507His	synonymous	Exon 7 of 10	NP_063945.2
	INPP5E	NM_001318502.2		c.1518C>T	p.His506His	synonymous	Exon 7 of 10	NP_001305431.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
INPP5E	ENST00000371712.4	TSL:1 MANE Select	c.1521C>T	p.His507His	synonymous	Exon 7 of 10	ENSP00000360777.3
INPP5E	ENST00000930360.1		c.1542C>T	p.His514His	synonymous	Exon 7 of 10	ENSP00000600419.1
INPP5E	ENST00000910890.1		c.1518C>T	p.His506His	synonymous	Exon 7 of 10	ENSP00000580949.1

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

15216

AN:

144000

Hom.:

1059

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0360

Gnomad AMI

AF:

0.0718

Gnomad AMR

AF:

0.191

Gnomad ASJ

AF:

0.116

Gnomad EAS

AF:

0.146

Gnomad SAS

AF:

0.146

Gnomad FIN

AF:

0.0708

Gnomad MID

AF:

0.129

Gnomad NFE

AF:

0.128

Gnomad OTH

AF:

0.105

GnomAD2 exomes

AF:

0.142

AC:

34747

AN:

244852

AF XY:

0.140

show subpopulations

Gnomad AFR exome

AF:

0.0350

Gnomad AMR exome

AF:

0.263

Gnomad ASJ exome

AF:

0.110

Gnomad EAS exome

AF:

0.146

Gnomad FIN exome

AF:

0.0699

Gnomad NFE exome

AF:

0.131

Gnomad OTH exome

AF:

0.129

GnomAD4 exome

AF:

0.132

AC:

190900

AN:

1441254

Hom.:

14594

Cov.:

AF XY:

0.133

AC XY:

95186

AN XY:

716898

show subpopulations

African (AFR)

AF:

0.0296

AC:

984

AN:

33288

American (AMR)

AF:

0.255

AC:

11115

AN:

43580

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

2679

AN:

25764

East Asian (EAS)

AF:

0.135

AC:

5301

AN:

39280

South Asian (SAS)

AF:

0.155

AC:

13134

AN:

84900

European-Finnish (FIN)

AF:

0.0709

AC:

3661

AN:

51602

Middle Eastern (MID)

AF:

0.115

AC:

659

AN:

5728

European-Non Finnish (NFE)

AF:

0.133

AC:

145778

AN:

1097510

Other (OTH)

AF:

0.127

AC:

7589

AN:

59602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

8907

17814

26721

35628

44535

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5386

10772

16158

21544

26930

<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:

0.106

AC:

15243

AN:

144108

Hom.:

1067

Cov.:

AF XY:

0.105

AC XY:

7366

AN XY:

69902

show subpopulations

African (AFR)

AF:

0.0363

AC:

1404

AN:

38696

American (AMR)

AF:

0.191

AC:

2705

AN:

14128

Ashkenazi Jewish (ASJ)

AF:

0.116

AC:

390

AN:

3376

East Asian (EAS)

AF:

0.146

AC:

697

AN:

4760

South Asian (SAS)

AF:

0.146

AC:

632

AN:

4320

European-Finnish (FIN)

AF:

0.0708

AC:

694

AN:

9798

Middle Eastern (MID)

AF:

0.126

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.128

AC:

8420

AN:

65922

Other (OTH)

AF:

0.104

AC:

202

AN:

1944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

596

1193

1789

2386

2982

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

170

340

510

680

850

<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:

0.0973

Hom.:

267

Bravo

AF:

0.116

Asia WGS

AF:

0.146

AC:

503

AN:

3438

EpiCase

AF:

0.131

EpiControl

AF:

0.129

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Joubert syndrome 1 (2)

Joubert syndrome (1)

MORM syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.055

(source)

DANN

Benign

0.53

PhyloP100

-1.4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over