dbSNP rs9288685: INPP5D:c.349+147T>C (chr2-233122404-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001017915.3(INPP5D):c.349+147T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 800,920 control chromosomes in the GnomAD database, including 94,622 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 0.49 ( 18432 hom., cov: 32)

Exomes 𝑓: 0.47 ( 76190 hom. )

Consequence

INPP5D
NM_001017915.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0760

Variant links:

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]

INPP5D links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
INPP5D	NM_001017915.3 link	c.349+147T>C	intron_variant	Intron 3 of 26	ENST00000445964.6	NP_001017915.1	Q92835-1
INPP5D	NM_005541.5 link	c.349+147T>C	intron_variant	Intron 3 of 26		NP_005532.2	Q92835-2
INPP5D	XM_047444219.1 link	c.349+147T>C	intron_variant	Intron 3 of 25		XP_047300175.1
INPP5D	XM_047444220.1 link	c.349+147T>C	intron_variant	Intron 3 of 25		XP_047300176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5D	ENST00000445964.6 link	c.349+147T>C		intron_variant	Intron 3 of 26	1	NM_001017915.3	ENSP00000405338.2		Q92835-1

Frequencies

GnomAD3 genomes

AF:

0.488

AC:

74090

AN:

151910

Hom.:

18415

Cov.:

show subpopulations

Gnomad AFR

AF:

0.485

Gnomad AMI

AF:

0.560

Gnomad AMR

AF:

0.427

Gnomad ASJ

AF:

0.403

Gnomad EAS

AF:

0.343

Gnomad SAS

AF:

0.340

Gnomad FIN

AF:

0.649

Gnomad MID

AF:

0.459

Gnomad NFE

AF:

0.504

Gnomad OTH

AF:

0.451

GnomAD4 exome

AF:

0.474

AC:

307637

AN:

648892

Hom.:

76190

AF XY:

0.469

AC XY:

154527

AN XY:

329476

show subpopulations

Gnomad4 AFR exome

AF:

0.477

Gnomad4 AMR exome

AF:

0.417

Gnomad4 ASJ exome

AF:

0.393

Gnomad4 EAS exome

AF:

0.359

Gnomad4 SAS exome

AF:

0.341

Gnomad4 FIN exome

AF:

0.625

Gnomad4 NFE exome

AF:

0.492

Gnomad4 OTH exome

AF:

0.457

GnomAD4 genome

AF:

0.488

AC:

74147

AN:

152028

Hom.:

18432

Cov.:

AF XY:

0.489

AC XY:

36370

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.485

Gnomad4 AMR

AF:

0.426

Gnomad4 ASJ

AF:

0.403

Gnomad4 EAS

AF:

0.342

Gnomad4 SAS

AF:

0.339

Gnomad4 FIN

AF:

0.649

Gnomad4 NFE

AF:

0.504

Gnomad4 OTH

AF:

0.450

Alfa

AF:

0.492

Hom.:

28279

Bravo

AF:

0.475

Asia WGS

AF:

0.376

AC:

1312

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.8

DANN

Benign

0.49

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over