rs12987960

Positions:

• chr2-233199308-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001017915.3(INPP5D):​c.2975+932A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00663 in 103,234 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0066 (0 hom., cov: 22)
• Consequence: INPP5D NM_001017915.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0850

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INPP5D	NM_001017915.3	c.2975+932A>G		intron_variant		ENST00000445964.6	NP_001017915.1
INPP5D	NM_005541.5	c.2972+932A>G		intron_variant			NP_005532.2
INPP5D	XM_047444219.1	c.2975+932A>G		intron_variant			XP_047300175.1
INPP5D	XM_047444220.1	c.2972+932A>G		intron_variant			XP_047300176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INPP5D	ENST00000445964.6	c.2975+932A>G		intron_variant		1	NM_001017915.3	ENSP00000405338	P5
INPP5D	ENST00000359570.9	c.2972+932A>G		intron_variant		1		ENSP00000352575	A2
INPP5D	ENST00000415617.5	c.1838+932A>G		intron_variant		5		ENSP00000397421
INPP5D	ENST00000417661.1	c.341+932A>G		intron_variant		3		ENSP00000414835

Frequencies

GnomAD3 genomes AF: 0.00662 AC: 683 AN: 103180 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00523

Gnomad AMI AF: 0.00207

Gnomad AMR AF: 0.00562

Gnomad ASJ AF: 0.00838

Gnomad EAS AF: 0.00285

Gnomad SAS AF: 0.00877

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.0149

Gnomad NFE AF: 0.00805

Gnomad OTH AF: 0.00611

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

GnomAD4 genome AF: 0.00663 AC: 684 AN: 103234 Hom.: 0 Cov.: 22 AF XY: 0.00644 AC XY: 323 AN XY: 50174

Gnomad4 AFR AF: 0.00522

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00838

Gnomad4 EAS AF: 0.00285

Gnomad4 SAS AF: 0.00881

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.00805

Gnomad4 OTH AF: 0.00671

Alfa AF: 0.0696 Hom.: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.2
DANN	Benign	0.22

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: rs12987960; hg19: chr2-234107954;