20-34928826-C-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000178.4(GSS):​c.*2G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000364 in 1,614,060 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00051 ( 1 hom., cov: 31)
Exomes 𝑓: 0.00035 ( 6 hom. )

Consequence

GSS
NM_000178.4 3_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.71

Publications

3 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: Benign. The variant received -18 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.31).
BP6
Variant 20-34928826-C-T is Benign according to our data. Variant chr20-34928826-C-T is described in ClinVar as [Benign]. Clinvar id is 338292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000506 (77/152224) while in subpopulation EAS AF = 0.0139 (72/5192). AF 95% confidence interval is 0.0113. There are 1 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GSSNM_000178.4 linkc.*2G>A 3_prime_UTR_variant Exon 13 of 13 ENST00000651619.1 NP_000169.1 P48637-1V9HWJ1
GSSNM_001322494.1 linkc.*2G>A 3_prime_UTR_variant Exon 13 of 13 NP_001309423.1 P48637-1V9HWJ1
GSSNM_001322495.1 linkc.*2G>A 3_prime_UTR_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.*2G>A 3_prime_UTR_variant Exon 13 of 13 NM_000178.4 ENSP00000498303.1 P48637-1

Frequencies

GnomAD3 genomes
AF:
0.000506
AC:
77
AN:
152106
Hom.:
1
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0138
Gnomad SAS
AF:
0.00104
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00105
AC:
264
AN:
251372
AF XY:
0.00104
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0130
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000350
AC:
511
AN:
1461836
Hom.:
6
Cov.:
31
AF XY:
0.000373
AC XY:
271
AN XY:
727212
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0106
AC:
421
AN:
39700
South Asian (SAS)
AF:
0.000730
AC:
63
AN:
86250
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5744
European-Non Finnish (NFE)
AF:
0.00000270
AC:
3
AN:
1111998
Other (OTH)
AF:
0.000397
AC:
24
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.484
Heterozygous variant carriers
0
34
68
103
137
171
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
10
20
30
40
50
<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:
0.000506
AC:
77
AN:
152224
Hom.:
1
Cov.:
31
AF XY:
0.000578
AC XY:
43
AN XY:
74414
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41534
American (AMR)
AF:
0.00
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.0139
AC:
72
AN:
5192
South Asian (SAS)
AF:
0.00104
AC:
5
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10596
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68006
Other (OTH)
AF:
0.00
AC:
0
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.494
Heterozygous variant carriers
0
3
6
10
13
16
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:
0.0000424
Hom.:
0
Bravo
AF:
0.000699
Asia WGS
AF:
0.00318
AC:
11
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Inherited glutathione synthetase deficiency Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.31
CADD
Benign
10
DANN
Benign
0.85
PhyloP100
2.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Mutation Taster
=100/0
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: rs36000727; hg19: chr20-33516629; API