rs35349669

Variant names:

• chr2-233159830-C-T
• rs35349669
• NM_001017915.3:c.1137+1411C>T

Variant summary

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

The NM_001017915.3(INPP5D):​c.1137+1411C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 152,000 control chromosomes in the GnomAD database, including 11,522 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 0.35 (11522 hom., cov: 31)
• Consequence: INPP5D NM_001017915.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.580

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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5D	NM_001017915.3	c.1137+1411C>T		intron_variant	Intron 10 of 26	ENST00000445964.6	NP_001017915.1
INPP5D	NM_005541.5	c.1134+1411C>T		intron_variant	Intron 10 of 26		NP_005532.2
INPP5D	XM_047444219.1	c.1137+1411C>T		intron_variant	Intron 10 of 25		XP_047300175.1
INPP5D	XM_047444220.1	c.1134+1411C>T		intron_variant	Intron 10 of 25		XP_047300176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5D	ENST00000445964.6	c.1137+1411C>T		intron_variant	Intron 10 of 26	1	NM_001017915.3	ENSP00000405338.2
INPP5D	ENST00000359570.9	c.1134+1411C>T		intron_variant	Intron 10 of 26	1		ENSP00000352575.7

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53082 AN: 151882 Hom.: 11521 Cov.: 31

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.572

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.0208

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.320

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

GnomAD4 genome AF: 0.349 AC: 53084 AN: 152000 Hom.: 11522 Cov.: 31 AF XY: 0.347 AC XY: 25790 AN XY: 74288

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.333

Gnomad4 ASJ AF: 0.349

Gnomad4 EAS AF: 0.0206

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.540

Gnomad4 NFE AF: 0.487

Gnomad4 OTH AF: 0.316

Alfa AF: 0.383 Hom.: 2394

Bravo AF: 0.324

Asia WGS AF: 0.137 AC: 481 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.8
DANN	Benign	0.38

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: rs35349669; hg19: chr2-234068476;