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GeneBe

4-142122213-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001101669.3(INPP4B):c.2050G>A(p.Val684Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000372 in 1,611,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

INPP4B
NM_001101669.3 missense

Scores

4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.61
Variant links:
Genes affected
INPP4B (HGNC:6075): (inositol polyphosphate-4-phosphatase type II B) INPP4B encodes the inositol polyphosphate 4-phosphatase type II, one of the enzymes involved in phosphatidylinositol signaling pathways. This enzyme removes the phosphate group at position 4 of the inositol ring from inositol 3,4-bisphosphate. There is limited data to suggest that the human type II enzyme is subject to alternative splicing, as has been established for the type I enzyme. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.02214545).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
INPP4BNM_001101669.3 linkuse as main transcriptc.2050G>A p.Val684Ile missense_variant 21/26 ENST00000262992.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
INPP4BENST00000262992.9 linkuse as main transcriptc.2050G>A p.Val684Ile missense_variant 21/265 NM_001101669.3 P3O15327-1

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152088
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000133
AC:
33
AN:
248172
Hom.:
0
AF XY:
0.000112
AC XY:
15
AN XY:
134200
show subpopulations
Gnomad AFR exome
AF:
0.000311
Gnomad AMR exome
AF:
0.0000298
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00127
Gnomad SAS exome
AF:
0.0000663
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000888
Gnomad OTH exome
AF:
0.000167
GnomAD4 exome
AF:
0.0000295
AC:
43
AN:
1459190
Hom.:
0
Cov.:
30
AF XY:
0.0000303
AC XY:
22
AN XY:
725864
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.0000225
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000531
Gnomad4 SAS exome
AF:
0.0000699
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000720
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152206
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74430
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00194
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000928
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000157
AC:
19
EpiCase
AF:
0.0000546
EpiControl
AF:
0.0000595

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 26, 2022The c.2050G>A (p.V684I) alteration is located in exon 22 (coding exon 18) of the INPP4B gene. This alteration results from a G to A substitution at nucleotide position 2050, causing the valine (V) at amino acid position 684 to be replaced by an isoleucine (I). 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
Benign
0.075
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.44
Cadd
Benign
23
Dann
Uncertain
1.0
DEOGEN2
Benign
0.13
T;T;T;T;T;.;T
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.82
D
M_CAP
Benign
0.0047
T
MetaRNN
Benign
0.022
T;T;T;T;T;T;T
MetaSVM
Benign
-1.2
T
MutationAssessor
Benign
1.4
L;L;L;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.62
N;N;N;N;N;N;N
REVEL
Benign
0.084
Sift
Benign
0.27
T;T;T;T;T;T;T
Sift4G
Benign
0.15
T;T;T;T;.;.;T
Polyphen
0.98
D;D;D;.;.;.;.
Vest4
0.22
MVP
0.24
MPC
0.22
ClinPred
0.054
T
GERP RS
5.9
Varity_R
0.087
gMVP
0.46

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

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

Other links and lift over

dbSNP: rs199940140; hg19: chr4-143043366; COSMIC: COSV53728894; API