rs1057258

Positions:

• chr2-233206983-C-T

Variant summary

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

The NM_001017915.3(INPP5D):​c.*275C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 434,028 control chromosomes in the GnomAD database, including 16,597 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 0.29 (8475 hom., cov: 32)
  • Exomes 𝑓: 0.22 (8122 hom.)
• Consequence: INPP5D NM_001017915.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.10

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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INPP5D	NM_001017915.3	c.*275C>T		3_prime_UTR_variant	27/27	ENST00000445964.6	NP_001017915.1
INPP5D	NM_005541.5	c.*275C>T		3_prime_UTR_variant	27/27		NP_005532.2
INPP5D	XM_047444219.1	c.*226C>T		3_prime_UTR_variant	26/26		XP_047300175.1
INPP5D	XM_047444220.1	c.*226C>T		3_prime_UTR_variant	26/26		XP_047300176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INPP5D	ENST00000445964.6	c.*275C>T		3_prime_UTR_variant	27/27	1	NM_001017915.3	ENSP00000405338.2
INPP5D	ENST00000359570.9	c.*275C>T		3_prime_UTR_variant	27/27	1		ENSP00000352575.7
INPP5D	ENST00000415617.5	c.*275C>T		3_prime_UTR_variant	17/17	5		ENSP00000397421.1
INPP5D	ENST00000417661.1	c.*226C>T		downstream_gene_variant		3		ENSP00000414835.1

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44398 AN: 151890 Hom.: 8435 Cov.: 32

Gnomad AFR AF: 0.537

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.224 AC: 63046 AN: 282020 Hom.: 8122 Cov.: 0 AF XY: 0.229 AC XY: 34166 AN XY: 149360

Gnomad4 AFR exome AF: 0.543

Gnomad4 AMR exome AF: 0.258

Gnomad4 ASJ exome AF: 0.203

Gnomad4 EAS exome AF: 0.376

Gnomad4 SAS exome AF: 0.311

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.183

Gnomad4 OTH exome AF: 0.239

GnomAD4 genome AF: 0.293 AC: 44489 AN: 152008 Hom.: 8475 Cov.: 32 AF XY: 0.288 AC XY: 21362 AN XY: 74292

Gnomad4 AFR AF: 0.538

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.195

Gnomad4 EAS AF: 0.397

Gnomad4 SAS AF: 0.317

Gnomad4 FIN AF: 0.142

Gnomad4 NFE AF: 0.177

Gnomad4 OTH AF: 0.272

Alfa AF: 0.208 Hom.: 4050

Bravo AF: 0.314

Asia WGS AF: 0.379 AC: 1316 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.49
DANN	Benign	0.80

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: rs1057258; hg19: chr2-234115629;