rs34936112

Variant names:

• chr9-136432610-G-A
• rs34936112
• NM_019892.6:c.1280-24C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136432610-G-A
• chr9-136432610-G-T

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.1280-24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 1,436,530 control chromosomes in the GnomAD database, including 59,794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5216 hom., cov: 33)
  • Exomes 𝑓: 0.29 (54578 hom.)
• Consequence: INPP5E NM_019892.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.118
• Publications: 9 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=-0.81).
• BP6: Variant 9-136432610-G-A is Benign according to our data. Variant chr9-136432610-G-A is described in ClinVar as [Benign]. Clinvar id is 261191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5E	NM_019892.6	c.1280-24C>T		intron_variant	Intron 5 of 9	ENST00000371712.4	NP_063945.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5E	ENST00000371712.4	c.1280-24C>T		intron_variant	Intron 5 of 9	1	NM_019892.6	ENSP00000360777.3
INPP5E	ENST00000676019.1	c.1178-24C>T		intron_variant	Intron 5 of 9			ENSP00000501984.1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38623 AN: 151972 Hom.: 5215 Cov.: 33

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.0553

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.275

GnomAD2 exomes AF: 0.257 AC: 39111 AN: 152366 AF XY: 0.251

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.291

Gnomad ASJ exome AF: 0.323

Gnomad EAS exome AF: 0.0423

Gnomad FIN exome AF: 0.274

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.285 AC: 366135 AN: 1284440 Hom.: 54578 Cov.: 19 AF XY: 0.282 AC XY: 180019 AN XY: 638958

African (AFR) AF: 0.178 AC: 5222 AN: 29390

American (AMR) AF: 0.291 AC: 10339 AN: 35562

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 7923 AN: 24428

East Asian (EAS) AF: 0.0888 AC: 3137 AN: 35334

South Asian (SAS) AF: 0.171 AC: 13204 AN: 77236

European-Finnish (FIN) AF: 0.264 AC: 11712 AN: 44422

Middle Eastern (MID) AF: 0.249 AC: 1366 AN: 5478

European-Non Finnish (NFE) AF: 0.305 AC: 298354 AN: 978200

Other (OTH) AF: 0.274 AC: 14878 AN: 54390

GnomAD4 genome AF: 0.254 AC: 38642 AN: 152090 Hom.: 5216 Cov.: 33 AF XY: 0.250 AC XY: 18609 AN XY: 74348

African (AFR) AF: 0.183 AC: 7578 AN: 41508

American (AMR) AF: 0.297 AC: 4548 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1113 AN: 3466

East Asian (EAS) AF: 0.0549 AC: 284 AN: 5174

South Asian (SAS) AF: 0.170 AC: 822 AN: 4828

European-Finnish (FIN) AF: 0.251 AC: 2659 AN: 10574

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20688 AN: 67936

Other (OTH) AF: 0.276 AC: 582 AN: 2108

Alfa AF: 0.293 Hom.: 1213

Bravo AF: 0.253

Asia WGS AF: 0.147 AC: 511 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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	-0.81
CADD	Benign	6.1
DANN	Benign	0.72
PhyloP100		-0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34936112; hg19: chr9-139327062;