rs34302850

Variant names:

• chr9-136432612-A-G
• rs34302850
• NM_019892.6:c.1280-26T>C

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.1280-26T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,418,354 control chromosomes in the GnomAD database, including 57,931 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.25 (5217 hom., cov: 33)
  • Exomes 𝑓: 0.28 (52714 hom.)
• Consequence: INPP5E NM_019892.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.72
• Publications: 7 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-136432612-A-G is Benign according to our data. Variant chr9-136432612-A-G is described in ClinVar as Benign. ClinVar VariationId is 261192.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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	NM_019892.6	MANE Select	c.1280-26T>C		intron	N/A	NP_063945.2
	INPP5E	NM_001318502.2		c.1280-29T>C		intron	N/A	NP_001305431.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	ENST00000371712.4	TSL:1 MANE Select	c.1280-26T>C		intron	N/A	ENSP00000360777.3
	INPP5E	ENST00000676019.1		c.1178-26T>C		intron	N/A	ENSP00000501984.1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38630 AN: 151922 Hom.: 5216 Cov.: 33

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.0557

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: 0.256 AC: 39039 AN: 152248 AF XY: 0.250

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.291

Gnomad ASJ exome AF: 0.323

Gnomad EAS exome AF: 0.0424

Gnomad FIN exome AF: 0.271

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.282 AC: 356609 AN: 1266314 Hom.: 52714 Cov.: 19 AF XY: 0.278 AC XY: 175651 AN XY: 630720

African (AFR) AF: 0.176 AC: 5105 AN: 29088

American (AMR) AF: 0.291 AC: 10332 AN: 35538

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 7851 AN: 24294

East Asian (EAS) AF: 0.0888 AC: 3133 AN: 35300

South Asian (SAS) AF: 0.170 AC: 13110 AN: 76982

European-Finnish (FIN) AF: 0.263 AC: 11623 AN: 44194

Middle Eastern (MID) AF: 0.249 AC: 1358 AN: 5444

European-Non Finnish (NFE) AF: 0.301 AC: 289521 AN: 961674

Other (OTH) AF: 0.271 AC: 14576 AN: 53800

GnomAD4 genome AF: 0.254 AC: 38649 AN: 152040 Hom.: 5217 Cov.: 33 AF XY: 0.250 AC XY: 18613 AN XY: 74338

African (AFR) AF: 0.183 AC: 7581 AN: 41502

American (AMR) AF: 0.298 AC: 4549 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1113 AN: 3462

East Asian (EAS) AF: 0.0552 AC: 285 AN: 5160

South Asian (SAS) AF: 0.170 AC: 821 AN: 4822

European-Finnish (FIN) AF: 0.251 AC: 2661 AN: 10588

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

European-Non Finnish (NFE) AF: 0.305 AC: 20690 AN: 67910

Other (OTH) AF: 0.276 AC: 581 AN: 2106

Alfa AF: 0.289 Hom.: 1814

Bravo AF: 0.253

Asia WGS AF: 0.147 AC: 511 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.31
PhyloP100		-1.7
BranchPoint Hunter		0.0
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: rs34302850; hg19: chr9-139327064;