2-233123012-T-C

Position:

• chr2-233123012-T-C

Variant summary

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

The NM_001017915.3(INPP5D):​c.349+755T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 152,084 control chromosomes in the GnomAD database, including 12,928 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 0.40 (12928 hom., cov: 32)
• Consequence: INPP5D NM_001017915.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00700

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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5D	NM_001017915.3	c.349+755T>C		intron_variant		ENST00000445964.6
INPP5D	NM_005541.5	c.349+755T>C		intron_variant
INPP5D	XM_047444219.1	c.349+755T>C		intron_variant
INPP5D	XM_047444220.1	c.349+755T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5D	ENST00000445964.6	c.349+755T>C		intron_variant		1	NM_001017915.3	P5

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60651 AN: 151966 Hom.: 12932 Cov.: 32

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.538

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.377

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

GnomAD4 genome AF: 0.399 AC: 60651 AN: 152084 Hom.: 12928 Cov.: 32 AF XY: 0.405 AC XY: 30104 AN XY: 74344

Gnomad4 AFR AF: 0.260

Gnomad4 AMR AF: 0.382

Gnomad4 ASJ AF: 0.372

Gnomad4 EAS AF: 0.336

Gnomad4 SAS AF: 0.327

Gnomad4 FIN AF: 0.626

Gnomad4 NFE AF: 0.462

Gnomad4 OTH AF: 0.375

Alfa AF: 0.443 Hom.: 30703

Bravo AF: 0.379

Asia WGS AF: 0.340 AC: 1182 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.7
DANN	Benign	0.52

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: rs10193128; hg19: chr2-233987722;