NM_019892.6:c.*328T>C

Variant names:

• chr9-136429347-A-G
• rs35763810
• NM_019892.6:c.*328T>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.*328T>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 0.421 in 437,152 control chromosomes in the GnomAD database, including 40,394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14191 hom., cov: 32)
  • Exomes 𝑓: 0.42 (26203 hom.)
• Consequence: INPP5E NM_019892.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.405
• Publications: 12 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• MORM syndrome

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, ClinGen, Genomics England PanelApp, Ambry Genetics, 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=-0.95).
• BP6: Variant 9-136429347-A-G is Benign according to our data. Variant chr9-136429347-A-G is described in ClinVar as Benign. ClinVar VariationId is 365875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.522 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.*328T>C		3_prime_UTR	Exon 10 of 10	NP_063945.2
	INPP5E	NM_001318502.2		c.*328T>C		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.*328T>C		3_prime_UTR	Exon 10 of 10	ENSP00000360777.3	Q9NRR6-1
	INPP5E	ENST00000930360.1		c.*328T>C		3_prime_UTR	Exon 10 of 10	ENSP00000600419.1
	INPP5E	ENST00000910890.1		c.*328T>C		3_prime_UTR	Exon 10 of 10	ENSP00000580949.1

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64828 AN: 151856 Hom.: 14160 Cov.: 32

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.448

GnomAD4 exome AF: 0.418 AC: 119262 AN: 285178 Hom.: 26203 Cov.: 0 AF XY: 0.409 AC XY: 62421 AN XY: 152740

African (AFR) AF: 0.417 AC: 3526 AN: 8450

American (AMR) AF: 0.555 AC: 7513 AN: 13536

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 3616 AN: 8000

East Asian (EAS) AF: 0.213 AC: 3327 AN: 15620

South Asian (SAS) AF: 0.332 AC: 14248 AN: 42966

European-Finnish (FIN) AF: 0.337 AC: 4766 AN: 14126

Middle Eastern (MID) AF: 0.399 AC: 459 AN: 1150

European-Non Finnish (NFE) AF: 0.453 AC: 75042 AN: 165632

Other (OTH) AF: 0.431 AC: 6765 AN: 15698

GnomAD4 genome AF: 0.427 AC: 64910 AN: 151974 Hom.: 14191 Cov.: 32 AF XY: 0.421 AC XY: 31239 AN XY: 74268

African (AFR) AF: 0.418 AC: 17333 AN: 41452

American (AMR) AF: 0.532 AC: 8124 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1561 AN: 3466

East Asian (EAS) AF: 0.206 AC: 1066 AN: 5172

South Asian (SAS) AF: 0.327 AC: 1571 AN: 4808

European-Finnish (FIN) AF: 0.327 AC: 3458 AN: 10590

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.447 AC: 30380 AN: 67898

Other (OTH) AF: 0.447 AC: 942 AN: 2106

Alfa AF: 0.370 Hom.: 1719

Bravo AF: 0.442

Asia WGS AF: 0.316 AC: 1100 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Joubert syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.9
DANN	Benign	0.31
PhyloP100		-0.41
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: rs35763810; hg19: chr9-139323799;