2-233182512-T-C

Variant names:

• chr2-233182512-T-C
• rs4571051
• NM_001017915.3:c.2161+13T>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.2161+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.66 in 1,611,990 control chromosomes in the GnomAD database, including 358,132 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 0.73 (41843 hom., cov: 32)
  • Exomes 𝑓: 0.65 (316289 hom.)
• Consequence: INPP5D NM_001017915.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34
• Publications: 12 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 (EAS) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5D	NM_001017915.3	MANE Select	c.2161+13T>C		intron	N/A	NP_001017915.1	Q92835-1
	INPP5D	NM_005541.5		c.2158+13T>C		intron	N/A	NP_005532.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP5D	ENST00000445964.6	TSL:1 MANE Select	c.2161+13T>C		intron	N/A	ENSP00000405338.2	Q92835-1
	INPP5D	ENST00000359570.9	TSL:1	c.2158+13T>C		intron	N/A	ENSP00000352575.7	Q92835-2
	INPP5D	ENST00000415617.5	TSL:5	c.1024+13T>C		intron	N/A	ENSP00000397421.1	H0Y5Q9

Frequencies

GnomAD3 genomes AF: 0.730 AC: 110913 AN: 151978 Hom.: 41778 Cov.: 32

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.721

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.958

Gnomad SAS AF: 0.788

Gnomad FIN AF: 0.623

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.627

Gnomad OTH AF: 0.739

GnomAD2 exomes AF: 0.704 AC: 175327 AN: 249158 AF XY: 0.701

Gnomad AFR exome AF: 0.913

Gnomad AMR exome AF: 0.740

Gnomad ASJ exome AF: 0.673

Gnomad EAS exome AF: 0.965

Gnomad FIN exome AF: 0.614

Gnomad NFE exome AF: 0.624

Gnomad OTH exome AF: 0.685

GnomAD4 exome AF: 0.653 AC: 953676 AN: 1459894 Hom.: 316289 Cov.: 60 AF XY: 0.656 AC XY: 476135 AN XY: 726214

African (AFR) AF: 0.919 AC: 30753 AN: 33456

American (AMR) AF: 0.735 AC: 32827 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 17491 AN: 26060

East Asian (EAS) AF: 0.953 AC: 37747 AN: 39610

South Asian (SAS) AF: 0.769 AC: 66302 AN: 86196

European-Finnish (FIN) AF: 0.620 AC: 32960 AN: 53182

Middle Eastern (MID) AF: 0.750 AC: 4319 AN: 5760

European-Non Finnish (NFE) AF: 0.621 AC: 689616 AN: 1110718

Other (OTH) AF: 0.692 AC: 41661 AN: 60246

GnomAD4 genome AF: 0.730 AC: 111037 AN: 152096 Hom.: 41843 Cov.: 32 AF XY: 0.732 AC XY: 54432 AN XY: 74346

African (AFR) AF: 0.908 AC: 37704 AN: 41542

American (AMR) AF: 0.721 AC: 11025 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 2349 AN: 3468

East Asian (EAS) AF: 0.958 AC: 4963 AN: 5182

South Asian (SAS) AF: 0.788 AC: 3800 AN: 4822

European-Finnish (FIN) AF: 0.623 AC: 6572 AN: 10550

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.627 AC: 42569 AN: 67926

Other (OTH) AF: 0.741 AC: 1569 AN: 2116

Alfa AF: 0.668 Hom.: 28300

Bravo AF: 0.743

Asia WGS AF: 0.873 AC: 3032 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.20
DANN	Benign	0.47
PhyloP100		-1.3

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: rs4571051; hg19: chr2-234091158;