9-136433147-G-T

Variant names:

• chr9-136433147-G-T
• rs73566945
• NM_019892.6:c.1159+8C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_019892.6(INPP5E):​c.1159+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,452,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: INPP5E NM_019892.6 splice_region, intron
• Scores: Splicing: ADA: 0.00008166
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.284
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 9-136433147-G-T is Benign according to our data. Variant chr9-136433147-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1918244.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1159+8C>A		splice_region intron	N/A	NP_063945.2
	INPP5E	NM_001318502.2		c.1159+8C>A		splice_region intron	N/A	NP_001305431.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5E	ENST00000371712.4	TSL:1 MANE Select	c.1159+8C>A		splice_region intron	N/A	ENSP00000360777.3
	INPP5E	ENST00000930360.1		c.1180+8C>A		splice_region intron	N/A	ENSP00000600419.1
	INPP5E	ENST00000910890.1		c.1159+8C>A		splice_region intron	N/A	ENSP00000580949.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1452220 Hom.: 0 Cov.: 42 AF XY: 0.00000969 AC XY: 7 AN XY: 722672

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1110024

Other (OTH) AF: 0.00 AC: 0 AN: 60196

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.55
DANN	Benign	0.54
PhyloP100		-0.28

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000082
dbscSNV1_RF	Benign	0.012
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: rs73566945; hg19: chr9-139327599;