9-136430228-C-T

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.1802+49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,548,680 control chromosomes in the GnomAD database, including 18,274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1962 hom., cov: 33)

Exomes 𝑓: 0.15 ( 16312 hom. )

Consequence

INPP5E
NM_019892.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.126

Publications

10 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 9-136430228-C-T is Benign according to our data. Variant chr9-136430228-C-T is described in ClinVar as Benign. ClinVar VariationId is 261200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
INPP5E	NM_019892.6 link	c.1802+49G>A	intron_variant	Intron 9 of 9	ENST00000371712.4	NP_063945.2
INPP5E	NM_001318502.2 link	c.1799+49G>A	intron_variant	Intron 9 of 9		NP_001305431.1
INPP5E	XM_017014926.2 link	c.1802+49G>A	intron_variant	Intron 9 of 9		XP_016870415.1
INPP5E	XM_047423603.1 link	c.1799+49G>A	intron_variant	Intron 9 of 9		XP_047279559.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
INPP5E	ENST00000371712.4 link	c.1802+49G>A	intron_variant	Intron 9 of 9	1	NM_019892.6	ENSP00000360777.3
INPP5E	ENST00000676019.1 link	c.1700+49G>A	intron_variant	Intron 9 of 9			ENSP00000501984.1
INPP5E	ENST00000674693.1 link	n.*107G>A	downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.154

AC:

23435

AN:

152092

Hom.:

1948

Cov.:

show subpopulations

Gnomad AFR

AF:

0.177

Gnomad AMI

AF:

0.0768

Gnomad AMR

AF:

0.223

Gnomad ASJ

AF:

0.124

Gnomad EAS

AF:

0.148

Gnomad SAS

AF:

0.157

Gnomad FIN

AF:

0.0732

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.140

Gnomad OTH

AF:

0.155

GnomAD2 exomes

AF:

0.161

AC:

24945

AN:

154834

AF XY:

0.156

show subpopulations

Gnomad AFR exome

AF:

0.178

Gnomad AMR exome

AF:

0.271

Gnomad ASJ exome

AF:

0.114

Gnomad EAS exome

AF:

0.147

Gnomad FIN exome

AF:

0.0688

Gnomad NFE exome

AF:

0.144

Gnomad OTH exome

AF:

0.147

GnomAD4 exome

AF:

0.149

AC:

208116

AN:

1396470

Hom.:

16312

Cov.:

AF XY:

0.149

AC XY:

102456

AN XY:

688700

show subpopulations

African (AFR)

AF:

0.176

AC:

5542

AN:

31578

American (AMR)

AF:

0.272

AC:

9699

AN:

35678

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

2887

AN:

25156

East Asian (EAS)

AF:

0.135

AC:

4812

AN:

35728

South Asian (SAS)

AF:

0.163

AC:

12888

AN:

79198

European-Finnish (FIN)

AF:

0.0736

AC:

3511

AN:

47706

Middle Eastern (MID)

AF:

0.132

AC:

743

AN:

5640

European-Non Finnish (NFE)

AF:

0.148

AC:

159456

AN:

1077862

Other (OTH)

AF:

0.148

AC:

8578

AN:

57924

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

8841

17683

26524

35366

44207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5934

11868

17802

23736

29670

<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:

0.154

AC:

23488

AN:

152210

Hom.:

1962

Cov.:

AF XY:

0.152

AC XY:

11310

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.177

AC:

7366

AN:

41534

American (AMR)

AF:

0.223

AC:

3417

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.124

AC:

430

AN:

3470

East Asian (EAS)

AF:

0.148

AC:

763

AN:

5164

South Asian (SAS)

AF:

0.157

AC:

757

AN:

4826

European-Finnish (FIN)

AF:

0.0732

AC:

777

AN:

10612

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.140

AC:

9540

AN:

67980

Other (OTH)

AF:

0.154

AC:

326

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1042

2084

3125

4167

5209

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

250

500

750

1000

1250

<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:

0.146

Hom.:

715

Bravo

AF:

0.169

Asia WGS

AF:

0.166

AC:

579

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.7

(source)

DANN

Benign

0.59

PhyloP100

-0.13

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over