9-136439387-G-C

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.33C>G(p.Ser11Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,463,608 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S11S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.023 ( 168 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 104 hom. )

Consequence

INPP5E
NM_019892.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.44

Publications

2 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
MORM syndrome
Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, ClinGen, Genomics England PanelApp, Ambry Genetics, 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=-0.86).

BP6

Variant 9-136439387-G-C is Benign according to our data. Variant chr9-136439387-G-C is described in ClinVar as Benign. ClinVar VariationId is 129273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.43 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.075 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	NM_019892.6	MANE Select	c.33C>G	p.Ser11Ser	synonymous	Exon 1 of 10	NP_063945.2
	INPP5E	NM_001318502.2		c.33C>G	p.Ser11Ser	synonymous	Exon 1 of 10	NP_001305431.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INPP5E	ENST00000371712.4	TSL:1 MANE Select	c.33C>G	p.Ser11Ser	synonymous	Exon 1 of 10	ENSP00000360777.3	Q9NRR6-1
INPP5E	ENST00000930360.1		c.33C>G	p.Ser11Ser	synonymous	Exon 1 of 10	ENSP00000600419.1
INPP5E	ENST00000910890.1		c.33C>G	p.Ser11Ser	synonymous	Exon 1 of 10	ENSP00000580949.1

Frequencies

GnomAD3 genomes

AF:

0.0229

AC:

3475

AN:

152020

Hom.:

168

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0774

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00503

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0287

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.0167

GnomAD2 exomes

AF:

0.00231

AC:

173

AN:

74920

AF XY:

0.00168

show subpopulations

Gnomad AFR exome

AF:

0.0855

Gnomad AMR exome

AF:

0.00357

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00685

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000573

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00244

AC:

3200

AN:

1311480

Hom.:

104

Cov.:

AF XY:

0.00216

AC XY:

1395

AN XY:

645926

show subpopulations

African (AFR)

AF:

0.0839

AC:

2223

AN:

26498

American (AMR)

AF:

0.00480

AC:

119

AN:

24804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23030

East Asian (EAS)

AF:

0.00338

AC:

AN:

28996

South Asian (SAS)

AF:

0.000354

AC:

AN:

70530

European-Finnish (FIN)

AF:

0.0000601

AC:

AN:

33276

Middle Eastern (MID)

AF:

0.00592

AC:

AN:

3884

European-Non Finnish (NFE)

AF:

0.000262

AC:

274

AN:

1046070

Other (OTH)

AF:

0.00802

AC:

436

AN:

54392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

160

321

481

642

802

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<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:

0.0229

AC:

3478

AN:

152128

Hom.:

168

Cov.:

AF XY:

0.0219

AC XY:

1630

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0773

AC:

3208

AN:

41522

American (AMR)

AF:

0.0106

AC:

162

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00485

AC:

AN:

5158

South Asian (SAS)

AF:

0.000414

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.0342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000515

AC:

AN:

67958

Other (OTH)

AF:

0.0170

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

158

316

473

631

789

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.00406

Hom.:

Bravo

AF:

0.0260

Asia WGS

AF:

0.0120

AC:

AN:

3454

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Joubert syndrome (1)

Joubert syndrome 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.2

(source)

DANN

Benign

0.66

PhyloP100

-3.4

PromoterAI

-0.036

Neutral

(source)

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