rs8413

Variant names:

• chr9-136428859-T-C
• rs8413
• NM_019892.6:c.*816A>G

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.*816A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 152,382 control chromosomes in the GnomAD database, including 12,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12228 hom., cov: 32)
  • Exomes 𝑓: 0.33 (21 hom.)
• Consequence: INPP5E NM_019892.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.21
• Publications: 52 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=-0.91).
• BP6: Variant 9-136428859-T-C is Benign according to our data. Variant chr9-136428859-T-C is described in ClinVar as Benign. ClinVar VariationId is 365868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.484 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.*816A>G		3_prime_UTR	Exon 10 of 10	NP_063945.2
	INPP5E	NM_001318502.2		c.*816A>G		3_prime_UTR	Exon 10 of 10	NP_001305431.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	ENST00000371712.4	TSL:1 MANE Select	c.*816A>G		3_prime_UTR	Exon 10 of 10	ENSP00000360777.3
	INPP5E	ENST00000930360.1		c.*816A>G		3_prime_UTR	Exon 10 of 10	ENSP00000600419.1
	INPP5E	ENST00000910890.1		c.*816A>G		3_prime_UTR	Exon 10 of 10	ENSP00000580949.1

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60240 AN: 151968 Hom.: 12199 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.395

GnomAD4 exome AF: 0.328 AC: 97 AN: 296 Hom.: 21 Cov.: 0 AF XY: 0.317 AC XY: 45 AN XY: 142

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.438 AC: 56 AN: 128

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.256 AC: 20 AN: 78

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.256 AC: 21 AN: 82

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.397 AC: 60318 AN: 152086 Hom.: 12228 Cov.: 32 AF XY: 0.390 AC XY: 29028 AN XY: 74336

African (AFR) AF: 0.379 AC: 15726 AN: 41468

American (AMR) AF: 0.493 AC: 7545 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1172 AN: 3472

East Asian (EAS) AF: 0.206 AC: 1062 AN: 5164

South Asian (SAS) AF: 0.320 AC: 1542 AN: 4816

European-Finnish (FIN) AF: 0.322 AC: 3406 AN: 10574

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28607 AN: 67984

Other (OTH) AF: 0.395 AC: 834 AN: 2110

Alfa AF: 0.414 Hom.: 34019

Bravo AF: 0.407

Asia WGS AF: 0.310 AC: 1079 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Joubert syndrome 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.88
DANN	Benign	0.28
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs8413; hg19: chr9-139323311; COSMIC: COSV65496226;