rs10176895

Positions:

• chr2-233132224-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001017915.3(INPP5D):​c.665+1576G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 152,320 control chromosomes in the GnomAD database, including 137 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 (137 hom., cov: 33)
• Consequence: INPP5D NM_001017915.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.22

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INPP5D	NM_001017915.3	c.665+1576G>A		intron_variant		ENST00000445964.6	NP_001017915.1
INPP5D	NM_005541.5	c.662+1576G>A		intron_variant			NP_005532.2
INPP5D	XM_047444219.1	c.665+1576G>A		intron_variant			XP_047300175.1
INPP5D	XM_047444220.1	c.662+1576G>A		intron_variant			XP_047300176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INPP5D	ENST00000445964.6	c.665+1576G>A		intron_variant		1	NM_001017915.3	ENSP00000405338	P5
INPP5D	ENST00000359570.9	c.662+1576G>A		intron_variant		1		ENSP00000352575	A2
INPP5D	ENST00000451407.4	n.778+1576G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5865 AN: 152202 Hom.: 136 Cov.: 33

Gnomad AFR AF: 0.0547

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0343

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0143

Gnomad MID AF: 0.0380

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: 0.0386 AC: 5872 AN: 152320 Hom.: 137 Cov.: 33 AF XY: 0.0367 AC XY: 2735 AN XY: 74476

Gnomad4 AFR AF: 0.0548

Gnomad4 AMR AF: 0.0343

Gnomad4 ASJ AF: 0.0248

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.0143

Gnomad4 NFE AF: 0.0393

Gnomad4 OTH AF: 0.0411

Alfa AF: 0.0388 Hom.: 45

Bravo AF: 0.0408

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	-0.94
CADD	Benign	0.016
DANN	Benign	0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs10176895; hg19: chr2-233996934;