9-136431807-C-T

Variant names:

• chr9-136431807-C-T
• rs776348228
• NM_019892.6:c.1549+17G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_019892.6(INPP5E):​c.1549+17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,483,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000086 (0 hom., cov: 16)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: INPP5E NM_019892.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.652
• 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: 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-136431807-C-T is Benign according to our data. Variant chr9-136431807-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445883.

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.1549+17G>A		intron	N/A	NP_063945.2
	INPP5E	NM_001318502.2		c.1546+17G>A		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.1549+17G>A		intron	N/A	ENSP00000360777.3	Q9NRR6-1
	INPP5E	ENST00000930360.1		c.1570+17G>A		intron	N/A	ENSP00000600419.1
	INPP5E	ENST00000910890.1		c.1546+17G>A		intron	N/A	ENSP00000580949.1

Frequencies

GnomAD3 genomes AF: 0.00000863 AC: 1 AN: 115812 Hom.: 0 Cov.: 16

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000183

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000325 AC: 7 AN: 215118 AF XY: 0.0000168

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000602

Gnomad NFE exome AF: 0.0000635

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000132 AC: 18 AN: 1367584 Hom.: 0 Cov.: 34 AF XY: 0.0000118 AC XY: 8 AN XY: 680792

African (AFR) AF: 0.00 AC: 0 AN: 31384

American (AMR) AF: 0.00 AC: 0 AN: 41766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23898

East Asian (EAS) AF: 0.00 AC: 0 AN: 34528

South Asian (SAS) AF: 0.00 AC: 0 AN: 83230

European-Finnish (FIN) AF: 0.0000225 AC: 1 AN: 44392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4962

European-Non Finnish (NFE) AF: 0.0000153 AC: 16 AN: 1047620

Other (OTH) AF: 0.0000179 AC: 1 AN: 55804

GnomAD4 genome AF: 0.00000863 AC: 1 AN: 115812 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 55782

African (AFR) AF: 0.00 AC: 0 AN: 30160

American (AMR) AF: 0.00 AC: 0 AN: 11402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2806

East Asian (EAS) AF: 0.00 AC: 0 AN: 3640

South Asian (SAS) AF: 0.00 AC: 0 AN: 3124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.0000183 AC: 1 AN: 54554

Other (OTH) AF: 0.00 AC: 0 AN: 1476

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.33
PhyloP100		-0.65

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: rs776348228; hg19: chr9-139326259;