rs9288685

Variant names:

• chr2-233122404-T-C
• rs9288685
• NM_001017915.3:c.349+147T>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.349+147T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 800,920 control chromosomes in the GnomAD database, including 94,622 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 0.49 (18432 hom., cov: 32)
  • Exomes 𝑓: 0.47 (76190 hom.)
• Consequence: INPP5D NM_001017915.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0760
• Publications: 14 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5D	NM_001017915.3	c.349+147T>C		intron_variant	Intron 3 of 26	ENST00000445964.6	NP_001017915.1
INPP5D	NM_005541.5	c.349+147T>C		intron_variant	Intron 3 of 26		NP_005532.2
INPP5D	XM_047444219.1	c.349+147T>C		intron_variant	Intron 3 of 25		XP_047300175.1
INPP5D	XM_047444220.1	c.349+147T>C		intron_variant	Intron 3 of 25		XP_047300176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5D	ENST00000445964.6	c.349+147T>C		intron_variant	Intron 3 of 26	1	NM_001017915.3	ENSP00000405338.2

Frequencies

GnomAD3 genomes AF: 0.488 AC: 74090 AN: 151910 Hom.: 18415 Cov.: 32

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.451

GnomAD4 exome AF: 0.474 AC: 307637 AN: 648892 Hom.: 76190 AF XY: 0.469 AC XY: 154527 AN XY: 329476

African (AFR) AF: 0.477 AC: 7859 AN: 16478

American (AMR) AF: 0.417 AC: 8240 AN: 19760

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 5694 AN: 14504

East Asian (EAS) AF: 0.359 AC: 11309 AN: 31510

South Asian (SAS) AF: 0.341 AC: 15467 AN: 45402

European-Finnish (FIN) AF: 0.625 AC: 18614 AN: 29784

Middle Eastern (MID) AF: 0.401 AC: 944 AN: 2356

European-Non Finnish (NFE) AF: 0.492 AC: 224913 AN: 457180

Other (OTH) AF: 0.457 AC: 14597 AN: 31918

GnomAD4 genome AF: 0.488 AC: 74147 AN: 152028 Hom.: 18432 Cov.: 32 AF XY: 0.489 AC XY: 36370 AN XY: 74308

African (AFR) AF: 0.485 AC: 20124 AN: 41454

American (AMR) AF: 0.426 AC: 6512 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 1399 AN: 3470

East Asian (EAS) AF: 0.342 AC: 1767 AN: 5162

South Asian (SAS) AF: 0.339 AC: 1633 AN: 4824

European-Finnish (FIN) AF: 0.649 AC: 6862 AN: 10576

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.504 AC: 34247 AN: 67944

Other (OTH) AF: 0.450 AC: 951 AN: 2114

Alfa AF: 0.491 Hom.: 43126

Bravo AF: 0.475

Asia WGS AF: 0.376 AC: 1312 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.49
PhyloP100		-0.076

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: rs9288685; hg19: chr2-233987114;