rs10200271

Variant names:

• chr2-233132347-A-C
• rs10200271
• NM_001017915.3:c.665+1699A>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+1699A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 152,126 control chromosomes in the GnomAD database, including 139 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 (139 hom., cov: 32)
• Consequence: INPP5D NM_001017915.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.01
• Publications: 5 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=-1.04).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5D	NM_001017915.3	c.665+1699A>C		intron_variant	Intron 5 of 26	ENST00000445964.6	NP_001017915.1
INPP5D	NM_005541.5	c.662+1699A>C		intron_variant	Intron 5 of 26		NP_005532.2
INPP5D	XM_047444219.1	c.665+1699A>C		intron_variant	Intron 5 of 25		XP_047300175.1
INPP5D	XM_047444220.1	c.662+1699A>C		intron_variant	Intron 5 of 25		XP_047300176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5D	ENST00000445964.6	c.665+1699A>C		intron_variant	Intron 5 of 26	1	NM_001017915.3	ENSP00000405338.2
INPP5D	ENST00000359570.9	c.662+1699A>C		intron_variant	Intron 5 of 26	1		ENSP00000352575.7
INPP5D	ENST00000451407.4	n.778+1699A>C		intron_variant	Intron 5 of 5	2

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5913 AN: 152008 Hom.: 138 Cov.: 32

Gnomad AFR AF: 0.0548

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0351

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0412

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

GnomAD4 genome AF: 0.0389 AC: 5919 AN: 152126 Hom.: 139 Cov.: 32 AF XY: 0.0372 AC XY: 2767 AN XY: 74404

African (AFR) AF: 0.0549 AC: 2278 AN: 41494

American (AMR) AF: 0.0350 AC: 535 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 95 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4812

European-Finnish (FIN) AF: 0.0144 AC: 153 AN: 10606

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0396 AC: 2693 AN: 67972

Other (OTH) AF: 0.0413 AC: 87 AN: 2108

Alfa AF: 0.0411 Hom.: 271

Bravo AF: 0.0413

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.059
DANN	Benign	0.43
PhyloP100		-2.0

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: rs10200271; hg19: chr2-233997057;