NM_015917.3:c.136G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_015917.3(GSTK1):​c.136G>A​(p.Gly46Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

GSTK1
NM_015917.3 missense

Scores

6
9
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.56
Variant links:
Genes affected
GSTK1 (HGNC:16906): (glutathione S-transferase kappa 1) This gene encodes a member of the kappa class of the glutathione transferase superfamily of enzymes that function in cellular detoxification. The encoded protein is localized to the peroxisome and catalyzes the conjugation of glutathione to a wide range of hydrophobic substates facilitating the removal of these compounds from cells. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jan 2009]
TMEM139-AS1 (HGNC:40988): (TMEM139 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GSTK1NM_015917.3 linkc.136G>A p.Gly46Arg missense_variant Exon 2 of 8 ENST00000358406.10 NP_057001.1 Q9Y2Q3-1Q6FII1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GSTK1ENST00000358406.10 linkc.136G>A p.Gly46Arg missense_variant Exon 2 of 8 1 NM_015917.3 ENSP00000351181.5 Q9Y2Q3-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251444
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135900
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.0000267
AC:
39
AN:
1461750
Hom.:
0
Cov.:
30
AF XY:
0.0000261
AC XY:
19
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000719
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152272
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000144
Hom.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 20, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.136G>A (p.G46R) alteration is located in exon 2 (coding exon 2) of the GSTK1 gene. This alteration results from a G to A substitution at nucleotide position 136, causing the glycine (G) at amino acid position 46 to be replaced by an arginine (R). 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
0.59
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.30
T;.;.;D;.
Eigen
Pathogenic
0.68
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.94
D;D;D;D;D
M_CAP
Benign
0.0064
T
MetaRNN
Pathogenic
0.96
D;D;D;D;D
MetaSVM
Benign
-0.39
T
MutationAssessor
Pathogenic
3.6
.;H;H;H;H
PrimateAI
Uncertain
0.55
T
PROVEAN
Pathogenic
-7.5
D;D;D;D;D
REVEL
Uncertain
0.44
Sift
Uncertain
0.0010
D;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D
Polyphen
1.0, 1.0
.;D;D;D;D
Vest4
0.86, 0.85, 0.85, 0.79
MutPred
0.89
.;Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);
MVP
0.57
MPC
1.1
ClinPred
0.99
D
GERP RS
6.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.92
gMVP
0.94

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: rs532485693; hg19: chr7-142961242; API