rs35349669

Variant names:

• chr2-233159830-C-T
• rs35349669
• NM_001017915.3:c.1137+1411C>T

Variant summary

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

The NM_001017915.3(INPP5D):​c.1137+1411C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 152,000 control chromosomes in the GnomAD database, including 11,522 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 0.35 (11522 hom., cov: 31)
• Consequence: INPP5D NM_001017915.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.580
• Publications: 130 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.483 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.1137+1411C>T		intron	N/A	NP_001017915.1	Q92835-1
	INPP5D	NM_005541.5		c.1134+1411C>T		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.1137+1411C>T		intron	N/A	ENSP00000405338.2	Q92835-1
	INPP5D	ENST00000359570.9	TSL:1	c.1134+1411C>T		intron	N/A	ENSP00000352575.7	Q92835-2

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53082 AN: 151882 Hom.: 11521 Cov.: 31

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.572

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.0208

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.320

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

GnomAD4 genome AF: 0.349 AC: 53084 AN: 152000 Hom.: 11522 Cov.: 31 AF XY: 0.347 AC XY: 25790 AN XY: 74288

African (AFR) AF: 0.130 AC: 5409 AN: 41450

American (AMR) AF: 0.333 AC: 5083 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1210 AN: 3468

East Asian (EAS) AF: 0.0206 AC: 107 AN: 5188

South Asian (SAS) AF: 0.244 AC: 1177 AN: 4816

European-Finnish (FIN) AF: 0.540 AC: 5692 AN: 10548

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.487 AC: 33115 AN: 67950

Other (OTH) AF: 0.316 AC: 666 AN: 2106

Alfa AF: 0.414 Hom.: 24515

Bravo AF: 0.324

Asia WGS AF: 0.137 AC: 481 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.8
DANN	Benign	0.38
PhyloP100		0.58

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: rs35349669; hg19: chr2-234068476;