rs144347039

Variant names:

• chr9-136433125-A-T
• rs144347039
• NM_019892.6:c.1159+30T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.57
• Publications: 2 publications found

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

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6	c.1159+30T>A		intron_variant	Intron 4 of 9	ENST00000371712.4	NP_063945.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712.4	c.1159+30T>A		intron_variant	Intron 4 of 9	1	NM_019892.6	ENSP00000360777.3
INPP5E	ENST00000676019.1	c.1057+30T>A		intron_variant	Intron 4 of 9			ENSP00000501984.1

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2569 AN: 151564 Hom.: 40 Cov.: 34

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

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.: 54 AF XY: 0.0213 AC XY: 15474 AN XY: 725400

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: 9 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

GnomAD4 genome AF: 0.0169 AC: 2567 AN: 151682 Hom.: 40 Cov.: 34 AF XY: 0.0167 AC XY: 1237 AN XY: 74166

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: 0 AN: 5150

South Asian (SAS) AF: 0.00685 AC: 33 AN: 4820

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10610

Middle Eastern (MID) AF: 0.0445 AC: 13 AN: 292

European-Non Finnish (NFE) AF: 0.0215 AC: 1459 AN: 67924

Other (OTH) AF: 0.0276 AC: 58 AN: 2104

Alfa AF: 0.0297 Hom.: 14

Bravo AF: 0.0218

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 05, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-1.0
CADD	Benign	0.95
DANN	Benign	0.38
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs144347039; hg19: chr9-139327577;