20-34928864-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_ModerateBP6_ModerateBP7

The NM_000178.4(GSS):​c.1389G>A​(p.Ala463Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

GSS
NM_000178.4 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.532

Publications

0 publications found
Variant links:
Genes affected
GSS (HGNC:4624): (glutathione synthetase) Glutathione is important for a variety of biological functions, including protection of cells from oxidative damage by free radicals, detoxification of xenobiotics, and membrane transport. The protein encoded by this gene functions as a homodimer to catalyze the second step of glutathione biosynthesis, which is the ATP-dependent conversion of gamma-L-glutamyl-L-cysteine to glutathione. Defects in this gene are a cause of glutathione synthetase deficiency. [provided by RefSeq, Jul 2008]
GSS Gene-Disease associations (from GenCC):
  • inherited glutathione synthetase deficiency
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • glutathione synthetase deficiency with 5-oxoprolinuria
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.32).
BP6
Variant 20-34928864-C-T is Benign according to our data. Variant chr20-34928864-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2860594.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=-0.532 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GSSNM_000178.4 linkc.1389G>A p.Ala463Ala synonymous_variant Exon 13 of 13 ENST00000651619.1 NP_000169.1 P48637-1V9HWJ1
GSSNM_001322494.1 linkc.1389G>A p.Ala463Ala synonymous_variant Exon 13 of 13 NP_001309423.1 P48637-1V9HWJ1
GSSNM_001322495.1 linkc.1389G>A p.Ala463Ala synonymous_variant Exon 13 of 13 NP_001309424.1 P48637-1V9HWJ1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GSSENST00000651619.1 linkc.1389G>A p.Ala463Ala synonymous_variant Exon 13 of 13 NM_000178.4 ENSP00000498303.1 P48637-1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152124
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000118
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000103
AC:
26
AN:
251318
AF XY:
0.000103
show subpopulations
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000202
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000561
AC:
82
AN:
1461790
Hom.:
0
Cov.:
31
AF XY:
0.0000688
AC XY:
50
AN XY:
727184
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39698
South Asian (SAS)
AF:
0.0000812
AC:
7
AN:
86252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5700
European-Non Finnish (NFE)
AF:
0.0000621
AC:
69
AN:
1111996
Other (OTH)
AF:
0.0000662
AC:
4
AN:
60388
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.477
Heterozygous variant carriers
0
6
12
18
24
30
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152124
Hom.:
0
Cov.:
31
AF XY:
0.0000673
AC XY:
5
AN XY:
74322
show subpopulations
African (AFR)
AF:
0.0000483
AC:
2
AN:
41398
American (AMR)
AF:
0.00
AC:
0
AN:
15268
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000118
AC:
8
AN:
68030
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.495
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000823
Hom.:
0
Bravo
AF:
0.0000302
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Glutathione synthetase deficiency with 5-oxoprolinuria Benign:1
Feb 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.32
CADD
Benign
12
DANN
Benign
0.89
PhyloP100
-0.53
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Mutation Taster
=91/9
polymorphism

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

Other links and lift over

dbSNP: rs765311167; hg19: chr20-33516667; COSMIC: COSV99404475; COSMIC: COSV99404475; API