2-233132429-T-C

Variant names:

• chr2-233132429-T-C
• rs10189488
• NM_001017915.3:c.665+1781T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001017915.3(INPP5D):​c.665+1781T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 152,300 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.039 (135 hom., cov: 32)
• Consequence: INPP5D NM_001017915.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 2 publications found

Genes affected

INPP5D (HGNC:6079): (inositol polyphosphate-5-phosphatase D) This gene is a member of the inositol polyphosphate-5-phosphatase (INPP5) family and encodes a protein with an N-terminal SH2 domain, an inositol phosphatase domain, and two C-terminal protein interaction domains. Expression of this protein is restricted to hematopoietic cells where its movement from the cytosol to the plasma membrane is mediated by tyrosine phosphorylation. At the plasma membrane, the protein hydrolyzes the 5' phosphate from phosphatidylinositol (3,4,5)-trisphosphate and inositol-1,3,4,5-tetrakisphosphate, thereby affecting multiple signaling pathways. The protein is also partly localized to the nucleus, where it may be involved in nuclear inositol phosphate signaling processes. Overall, the protein functions as a negative regulator of myeloid cell proliferation and survival. Mutations in this gene are associated with defects and cancers of the immune system. Deficiencies in the encoded protein, SHIP1, have been associated with Inflammatory Bowel Disease types such as Crohn's Disease and Ulcerative Colitis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2020]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017915.3. 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
	INPP5D	NM_001017915.3	MANE Select	c.665+1781T>C		intron	N/A	NP_001017915.1
	INPP5D	NM_005541.5		c.662+1781T>C		intron	N/A	NP_005532.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5D	ENST00000445964.6	TSL:1 MANE Select	c.665+1781T>C		intron	N/A	ENSP00000405338.2
	INPP5D	ENST00000359570.9	TSL:1	c.662+1781T>C		intron	N/A	ENSP00000352575.7
	INPP5D	ENST00000451407.4	TSL:2	n.778+1781T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5858 AN: 152182 Hom.: 134 Cov.: 32

Gnomad AFR AF: 0.0546

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0343

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0393

Gnomad OTH AF: 0.0411

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0385 AC: 5865 AN: 152300 Hom.: 135 Cov.: 32 AF XY: 0.0366 AC XY: 2723 AN XY: 74482

African (AFR) AF: 0.0547 AC: 2273 AN: 41550

American (AMR) AF: 0.0342 AC: 524 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4826

European-Finnish (FIN) AF: 0.0142 AC: 151 AN: 10618

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0393 AC: 2672 AN: 68018

Other (OTH) AF: 0.0412 AC: 87 AN: 2114

Alfa AF: 0.0382 Hom.: 19

Bravo AF: 0.0408

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.20
PhyloP100		-1.0

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs10189488; hg19: chr2-233997139;