NM_019892.6:c.1248T>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.1248T>C(p.Thr416Thr) 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 1,612,540 control chromosomes in the GnomAD database, including 158,937 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 13784 hom., cov: 33)

Exomes 𝑓: 0.44 ( 145153 hom. )

Consequence

INPP5E
NM_019892.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.160

Publications

48 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:

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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=-0.53).

BP6

Variant 9-136432987-A-G is Benign according to our data. Variant chr9-136432987-A-G is described in ClinVar as Benign. ClinVar VariationId is 129265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.16 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.519 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.1248T>C	p.Thr416Thr	synonymous	Exon 5 of 10	NP_063945.2
	INPP5E	NM_001318502.2		c.1248T>C	p.Thr416Thr	synonymous	Exon 5 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.1248T>C	p.Thr416Thr	synonymous	Exon 5 of 10	ENSP00000360777.3	Q9NRR6-1
INPP5E	ENST00000930360.1		c.1269T>C	p.Thr423Thr	synonymous	Exon 5 of 10	ENSP00000600419.1
INPP5E	ENST00000910890.1		c.1248T>C	p.Thr416Thr	synonymous	Exon 5 of 10	ENSP00000580949.1

Frequencies

GnomAD3 genomes

AF:

0.421

AC:

63929

AN:

151936

Hom.:

13754

Cov.:

show subpopulations

Gnomad AFR

AF:

0.398

Gnomad AMI

AF:

0.389

Gnomad AMR

AF:

0.527

Gnomad ASJ

AF:

0.450

Gnomad EAS

AF:

0.206

Gnomad SAS

AF:

0.328

Gnomad FIN

AF:

0.327

Gnomad MID

AF:

0.415

Gnomad NFE

AF:

0.446

Gnomad OTH

AF:

0.442

GnomAD2 exomes

AF:

0.420

AC:

104353

AN:

248560

AF XY:

0.411

show subpopulations

Gnomad AFR exome

AF:

0.391

Gnomad AMR exome

AF:

0.570

Gnomad ASJ exome

AF:

0.440

Gnomad EAS exome

AF:

0.190

Gnomad FIN exome

AF:

0.333

Gnomad NFE exome

AF:

0.451

Gnomad OTH exome

AF:

0.435

GnomAD4 exome

AF:

0.441

AC:

644336

AN:

1460486

Hom.:

145153

Cov.:

AF XY:

0.437

AC XY:

317514

AN XY:

726490

show subpopulations

African (AFR)

AF:

0.396

AC:

13237

AN:

33458

American (AMR)

AF:

0.570

AC:

25401

AN:

44580

Ashkenazi Jewish (ASJ)

AF:

0.443

AC:

11564

AN:

26128

East Asian (EAS)

AF:

0.222

AC:

8804

AN:

39650

South Asian (SAS)

AF:

0.336

AC:

28941

AN:

86208

European-Finnish (FIN)

AF:

0.338

AC:

17868

AN:

52938

Middle Eastern (MID)

AF:

0.385

AC:

2220

AN:

5764

European-Non Finnish (NFE)

AF:

0.459

AC:

510428

AN:

1111416

Other (OTH)

AF:

0.429

AC:

25873

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

22194

44388

66582

88776

110970

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15244

30488

45732

60976

76220

<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:

64008

AN:

152054

Hom.:

13784

Cov.:

AF XY:

0.414

AC XY:

30786

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.398

AC:

16529

AN:

41480

American (AMR)

AF:

0.528

AC:

8081

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.450

AC:

1562

AN:

3470

East Asian (EAS)

AF:

0.206

AC:

1063

AN:

5164

South Asian (SAS)

AF:

0.328

AC:

1580

AN:

4820

European-Finnish (FIN)

AF:

0.327

AC:

3455

AN:

10578

Middle Eastern (MID)

AF:

0.425

AC:

125

AN:

294

European-Non Finnish (NFE)

AF:

0.446

AC:

30328

AN:

67930

Other (OTH)

AF:

0.441

AC:

931

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1973

3945

5918

7890

9863

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:

0.446

Hom.:

25663

Bravo

AF:

0.436

Asia WGS

AF:

0.319

AC:

1111

AN:

3478

ClinVar

ClinVar submissions

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

-0.53

CADD

Benign

(source)

DANN

Benign

0.55

PhyloP100

-0.16

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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