chr2-233133771-C-A

Position:

• chr2-233133771-C-A

Variant summary

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

The ENST00000445964.6(INPP5D):​c.665+3123C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 151,780 control chromosomes in the GnomAD database, including 17,279 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 0.47 (17279 hom., cov: 30)
• Consequence: INPP5D ENST00000445964.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0590

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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INPP5D	NM_001017915.3	c.665+3123C>A		intron_variant		ENST00000445964.6	NP_001017915.1
INPP5D	NM_005541.5	c.662+3123C>A		intron_variant			NP_005532.2
INPP5D	XM_047444219.1	c.665+3123C>A		intron_variant			XP_047300175.1
INPP5D	XM_047444220.1	c.662+3123C>A		intron_variant			XP_047300176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INPP5D	ENST00000445964.6	c.665+3123C>A		intron_variant		1	NM_001017915.3	ENSP00000405338	P5
INPP5D	ENST00000359570.9	c.662+3123C>A		intron_variant		1		ENSP00000352575	A2
INPP5D	ENST00000451407.4	n.778+3123C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.471 AC: 71470 AN: 151662 Hom.: 17266 Cov.: 30

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.579

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.499

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.513

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

GnomAD4 genome AF: 0.471 AC: 71522 AN: 151780 Hom.: 17279 Cov.: 30 AF XY: 0.464 AC XY: 34431 AN XY: 74136

Gnomad4 AFR AF: 0.542

Gnomad4 AMR AF: 0.404

Gnomad4 ASJ AF: 0.579

Gnomad4 EAS AF: 0.502

Gnomad4 SAS AF: 0.500

Gnomad4 FIN AF: 0.308

Gnomad4 NFE AF: 0.459

Gnomad4 OTH AF: 0.510

Alfa AF: 0.466 Hom.: 18659

Bravo AF: 0.481

Asia WGS AF: 0.457 AC: 1587 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.21
DANN	Benign	0.44

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: rs10933436; hg19: chr2-233998481;