2-233163905-T-C

Variant names:

• chr2-233163905-T-C
• NM_001017915.3:c.1437+2T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001017915.3(INPP5D):​c.1437+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: INPP5D NM_001017915.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.26

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5D	NM_001017915.3	c.1437+2T>C		splice_donor_variant, intron_variant	Intron 12 of 26	ENST00000445964.6	NP_001017915.1
INPP5D	NM_005541.5	c.1434+2T>C		splice_donor_variant, intron_variant	Intron 12 of 26		NP_005532.2
INPP5D	XM_047444219.1	c.1437+2T>C		splice_donor_variant, intron_variant	Intron 12 of 25		XP_047300175.1
INPP5D	XM_047444220.1	c.1434+2T>C		splice_donor_variant, intron_variant	Intron 12 of 25		XP_047300176.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5D	ENST00000445964.6	c.1437+2T>C		splice_donor_variant, intron_variant	Intron 12 of 26	1	NM_001017915.3	ENSP00000405338.2
INPP5D	ENST00000359570.9	c.1434+2T>C		splice_donor_variant, intron_variant	Intron 12 of 26	1		ENSP00000352575.7
INPP5D	ENST00000415617.5	c.300+2T>C		splice_donor_variant, intron_variant	Intron 2 of 16	5		ENSP00000397421.1
INPP5D	ENST00000493078.1	n.237T>C		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe combined immunodeficiency disease Uncertain:1

Mar 23, 2023

Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.88		Position offset: 21
DS_DL_spliceai		0.98		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-234072551;