chr2-233199308-A-G

Variant names:

• chr2-233199308-A-G
• rs12987960
• NM_001017915.3:c.2975+932A>G

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Variant has high frequency in the SAS (0.00737) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5D	NM_001017915.3	MANE Select	c.2975+932A>G		intron	N/A	NP_001017915.1
	INPP5D	NM_005541.5		c.2972+932A>G		intron	N/A	NP_005532.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5D	ENST00000445964.6	TSL:1 MANE Select	c.2975+932A>G		intron	N/A	ENSP00000405338.2
	INPP5D	ENST00000359570.9	TSL:1	c.2972+932A>G		intron	N/A	ENSP00000352575.7
	INPP5D	ENST00000415617.5	TSL:5	c.1838+932A>G		intron	N/A	ENSP00000397421.1

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00522 AC: 145 AN: 27790

American (AMR) AF: 0.00562 AC: 59 AN: 10506

Ashkenazi Jewish (ASJ) AF: 0.00838 AC: 22 AN: 2624

East Asian (EAS) AF: 0.00285 AC: 12 AN: 4212

South Asian (SAS) AF: 0.00881 AC: 28 AN: 3178

European-Finnish (FIN) AF: 0.00471 AC: 29 AN: 6156

Middle Eastern (MID) AF: 0.0160 AC: 3 AN: 188

European-Non Finnish (NFE) AF: 0.00805 AC: 375 AN: 46606

Other (OTH) AF: 0.00671 AC: 10 AN: 1490

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0696 Hom.: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.2
DANN	Benign	0.22
PhyloP100		0.085

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: rs12987960; hg19: chr2-234107954;