rs144347039

Variant names:

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+30T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0209 in 1,609,640 control chromosomes in the GnomAD database, including 501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 40 hom., cov: 34)

Exomes 𝑓: 0.021 ( 461 hom. )

Consequence

INPP5E
NM_019892.6 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.57

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 -20 ACMG points.

BP4

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

BP6

Variant 9-136433125-A-T is Benign according to our data. Variant chr9-136433125-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0556 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.1159+30T>A		intron	N/A	NP_063945.2
	INPP5E	NM_001318502.2		c.1159+30T>A		intron	N/A	NP_001305431.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
INPP5E	ENST00000371712.4	TSL:1 MANE Select	c.1159+30T>A	intron	N/A	ENSP00000360777.3	Q9NRR6-1
INPP5E	ENST00000930360.1		c.1180+30T>A	intron	N/A	ENSP00000600419.1
INPP5E	ENST00000910890.1		c.1159+30T>A	intron	N/A	ENSP00000580949.1

Frequencies

GnomAD3 genomes

AF:

0.0169

AC:

2569

AN:

151564

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00714

Gnomad AMI

AF:

0.0285

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:

0.0478

Gnomad NFE

AF:

0.0215

Gnomad OTH

AF:

0.0279

GnomAD2 exomes

AF:

0.0185

AC:

4537

AN:

245098

AF XY:

0.0190

show subpopulations

Gnomad AFR exome

AF:

0.00766

Gnomad AMR exome

AF:

0.0171

Gnomad ASJ exome

AF:

0.0800

Gnomad EAS exome

AF:

0.000659

Gnomad FIN exome

AF:

0.00302

Gnomad NFE exome

AF:

0.0228

Gnomad OTH exome

AF:

0.0285

GnomAD4 exome

AF:

0.0213

AC:

31058

AN:

1457958

Hom.:

461

Cov.:

AF XY:

0.0213

AC XY:

15474

AN XY:

725400

show subpopulations

African (AFR)

AF:

0.00743

AC:

248

AN:

33378

American (AMR)

AF:

0.0178

AC:

797

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0801

AC:

2091

AN:

26114

East Asian (EAS)

AF:

0.000227

AC:

AN:

39662

South Asian (SAS)

AF:

0.00822

AC:

709

AN:

86250

European-Finnish (FIN)

AF:

0.00377

AC:

189

AN:

50128

Middle Eastern (MID)

AF:

0.0609

AC:

351

AN:

5768

European-Non Finnish (NFE)

AF:

0.0226

AC:

25173

AN:

1111664

Other (OTH)

AF:

0.0247

AC:

1491

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

1613

3226

4839

6452

8065

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

968

1936

2904

3872

4840

<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:

0.0169

AC:

2567

AN:

151682

Hom.:

Cov.:

AF XY:

0.0167

AC XY:

1237

AN XY:

74166

show subpopulations

African (AFR)

AF:

0.00712

AC:

293

AN:

41150

American (AMR)

AF:

0.0245

AC:

373

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.0810

AC:

281

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00685

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00292

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0445

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0215

AC:

1459

AN:

67924

Other (OTH)

AF:

0.0276

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

122

243

365

486

608

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:

0.0297

Hom.:

Bravo

AF:

0.0218

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.95

(source)

DANN

Benign

0.38

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

Other links and lift over