10-119805413-C-A

Variant summary

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

The NM_014937.4(INPP5F):​c.1271C>A​(p.Thr424Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,182 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

INPP5F
NM_014937.4 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.12
Variant links:
Genes affected
INPP5F (HGNC:17054): (inositol polyphosphate-5-phosphatase F) The protein encoded by this gene is an inositol 1,4,5-trisphosphate (InsP3) 5-phosphatase and contains a Sac domain. The activity of this protein is specific for phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2011]
PHACTR2P1 (HGNC:49488): (phosphatase and actin regulator 2 pseudogene 1)

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=0.065874666).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
INPP5FNM_014937.4 linkc.1271C>A p.Thr424Lys missense_variant Exon 11 of 20 ENST00000650623.2 NP_055752.1 Q9Y2H2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
INPP5FENST00000650623.2 linkc.1271C>A p.Thr424Lys missense_variant Exon 11 of 20 NM_014937.4 ENSP00000497527.1 Q9Y2H2-1

Frequencies

GnomAD3 genomes
AF:
0.000289
AC:
44
AN:
152150
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000990
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000716
AC:
18
AN:
251304
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135830
show subpopulations
Gnomad AFR exome
AF:
0.000862
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000390
AC:
57
AN:
1460914
Hom.:
0
Cov.:
30
AF XY:
0.0000234
AC XY:
17
AN XY:
726806
show subpopulations
Gnomad4 AFR exome
AF:
0.00123
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.000296
AC:
45
AN:
152268
Hom.:
1
Cov.:
32
AF XY:
0.000242
AC XY:
18
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.00101
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000161
Hom.:
0
Bravo
AF:
0.000302
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000494
AC:
6

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 11, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1271C>A (p.T424K) alteration is located in exon 11 (coding exon 11) of the INPP5F gene. This alteration results from a C to A substitution at nucleotide position 1271, causing the threonine (T) at amino acid position 424 to be replaced by a lysine (K). 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
0.62
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
22
DANN
Benign
0.97
DEOGEN2
Benign
0.19
T;.;T;.;.;.;.
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.96
.;D;D;D;.;D;D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.066
T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.020
N;.;N;.;.;.;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-1.6
N;.;.;.;.;.;.
REVEL
Benign
0.20
Sift
Benign
0.18
T;.;.;.;.;.;.
Sift4G
Benign
0.34
T;.;.;.;.;.;.
Polyphen
0.98
D;.;D;.;.;.;.
Vest4
0.65
MVP
0.42
MPC
0.32
ClinPred
0.056
T
GERP RS
5.7
Varity_R
0.19
gMVP
0.62

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.

Other links and lift over

dbSNP: rs141716473; hg19: chr10-121564925; API