9-136428749-A-G

Position:

chr9-136428749-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_019892.6(INPP5E):c.*926T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 152,640 control chromosomes in the GnomAD database, including 1,179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1175 hom., cov: 32)

Exomes 𝑓: 0.099 ( 4 hom. )

Consequence

INPP5E
NM_019892.6 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.227

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 9-136428749-A-G is Benign according to our data. Variant chr9-136428749-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 365866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein	UniProt
INPP5E	NM_019892.6 linkuse as main transcript	c.*926T>C	3_prime_UTR_variant	10/10	ENST00000371712.4	NP_063945.2	Q9NRR6-1
INPP5E	NM_001318502.2 linkuse as main transcript	c.*926T>C	3_prime_UTR_variant	10/10		NP_001305431.1	Q9NRR6
INPP5E	XM_017014926.2 linkuse as main transcript	c.*1005T>C	3_prime_UTR_variant	10/10		XP_016870415.1
INPP5E	XM_047423603.1 linkuse as main transcript	c.*1005T>C	3_prime_UTR_variant	10/10		XP_047279559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712 linkuse as main transcript	c.*926T>C		3_prime_UTR_variant	10/10	1	NM_019892.6	ENSP00000360777.3		Q9NRR6-1
INPP5E	ENST00000676019 linkuse as main transcript	c.*926T>C		3_prime_UTR_variant	10/10			ENSP00000501984.1		Q9NRR6-2

Frequencies

GnomAD3 genomes

AF:

0.113

AC:

17169

AN:

152118

Hom.:

1167

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0544

Gnomad AMI

AF:

0.0749

Gnomad AMR

AF:

0.197

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.150

Gnomad SAS

AF:

0.154

Gnomad FIN

AF:

0.0728

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.130

Gnomad OTH

AF:

0.115

GnomAD4 exome

AF:

0.0990

AC:

AN:

404

Hom.:

Cov.:

AF XY:

0.107

AC XY:

AN XY:

224

show subpopulations

Gnomad4 EAS exome

AF:

0.157

Gnomad4 FIN exome

AF:

0.0714

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.113

AC:

17203

AN:

152236

Hom.:

1175

Cov.:

AF XY:

0.113

AC XY:

8401

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0548

Gnomad4 AMR

AF:

0.198

Gnomad4 ASJ

AF:

0.117

Gnomad4 EAS

AF:

0.149

Gnomad4 SAS

AF:

0.154

Gnomad4 FIN

AF:

0.0728

Gnomad4 NFE

AF:

0.130

Gnomad4 OTH

AF:

0.115

Alfa

AF:

0.133

Hom.:

1865

Bravo

AF:

0.122

Asia WGS

AF:

0.158

AC:

550

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Joubert syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.5

DANN

Benign

0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over