2-190360158-C-T

Variant summary

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

The NM_001128928.2(INPP1):c.56C>T(p.Ala19Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: INPP1 NM_001128928.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.31

Genes affected

INPP1 (HGNC:6071): (inositol polyphosphate-1-phosphatase) This gene encodes the enzyme inositol polyphosphate-1-phosphatase, one of the enzymes involved in phosphatidylinositol signaling pathways. This enzyme removes the phosphate group at position 1 of the inositol ring from the polyphosphates inositol 1,4-bisphosphate and inositol 1,3,4-trisphophosphate. [provided by RefSeq, Jul 2008]

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/exons	MANE	UniProt
INPP1	NM_001128928.2	c.56C>T	p.Ala19Val	missense_variant	3/7	ENST00000392329.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP1	ENST00000392329.7	c.56C>T	p.Ala19Val	missense_variant	3/7	5	NM_001128928.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251268 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461768 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

The c.56C>T (p.A19V) alteration is located in exon 3 (coding exon 1) of the INPP1 gene. This alteration results from a C to T substitution at nucleotide position 56, causing the alanine (A) at amino acid position 19 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.26	T;T;.;.;T;.;.;T;T;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.7	M;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;T;D;D;T;D;D;D
Polyphen		1.0	D;D;.;.;.;.;.;.;.;.
Vest4		0.64
MutPred		0.69		Loss of disorder (P = 0.0685);Loss of disorder (P = 0.0685);Loss of disorder (P = 0.0685);Loss of disorder (P = 0.0685);Loss of disorder (P = 0.0685);Loss of disorder (P = 0.0685);Loss of disorder (P = 0.0685);Loss of disorder (P = 0.0685);Loss of disorder (P = 0.0685);Loss of disorder (P = 0.0685);
MVP		0.58
MPC		0.74
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.70
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs770963149; hg19: chr2-191224884;