chr20-34945933-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000178.4(GSS):c.275+20T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 1,611,838 control chromosomes in the GnomAD database, including 323,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.68 ( 36631 hom., cov: 33)

Exomes 𝑓: 0.62 ( 286520 hom. )

Consequence

GSS
NM_000178.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.60

Publications

24 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)

GSS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 20-34945933-A-C is Benign according to our data. Variant chr20-34945933-A-C is described in ClinVar as Benign. ClinVar VariationId is 255474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GSS	NM_000178.4 link	c.275+20T>G	intron_variant	Intron 3 of 12	ENST00000651619.1	NP_000169.1	P48637-1V9HWJ1
GSS	NM_001322494.1 link	c.275+20T>G	intron_variant	Intron 3 of 12		NP_001309423.1	P48637-1V9HWJ1
GSS	NM_001322495.1 link	c.275+20T>G	intron_variant	Intron 3 of 12		NP_001309424.1	P48637-1V9HWJ1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSS	ENST00000651619.1 link	c.275+20T>G		intron_variant	Intron 3 of 12		NM_000178.4	ENSP00000498303.1		P48637-1

Frequencies

GnomAD3 genomes

AF:

0.676

AC:

102712

AN:

151970

Hom.:

36571

Cov.:

show subpopulations

Gnomad AFR

AF:

0.906

Gnomad AMI

AF:

0.464

Gnomad AMR

AF:

0.474

Gnomad ASJ

AF:

0.629

Gnomad EAS

AF:

0.453

Gnomad SAS

AF:

0.740

Gnomad FIN

AF:

0.596

Gnomad MID

AF:

0.642

Gnomad NFE

AF:

0.612

Gnomad OTH

AF:

0.627

GnomAD2 exomes

AF:

0.600

AC:

150741

AN:

251084

AF XY:

0.612

show subpopulations

Gnomad AFR exome

AF:

0.919

Gnomad AMR exome

AF:

0.307

Gnomad ASJ exome

AF:

0.636

Gnomad EAS exome

AF:

0.484

Gnomad FIN exome

AF:

0.608

Gnomad NFE exome

AF:

0.620

Gnomad OTH exome

AF:

0.592

GnomAD4 exome

AF:

0.621

AC:

905987

AN:

1459750

Hom.:

286520

Cov.:

AF XY:

0.624

AC XY:

453408

AN XY:

726278

show subpopulations

African (AFR)

AF:

0.921

AC:

30800

AN:

33442

American (AMR)

AF:

0.326

AC:

14555

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.637

AC:

16629

AN:

26108

East Asian (EAS)

AF:

0.443

AC:

17573

AN:

39678

South Asian (SAS)

AF:

0.742

AC:

63930

AN:

86168

European-Finnish (FIN)

AF:

0.604

AC:

32197

AN:

53264

Middle Eastern (MID)

AF:

0.641

AC:

3674

AN:

5728

European-Non Finnish (NFE)

AF:

0.620

AC:

688463

AN:

1110334

Other (OTH)

AF:

0.633

AC:

38166

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

15100

30199

45299

60398

75498

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18458

36916

55374

73832

92290

<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:

0.676

AC:

102813

AN:

152088

Hom.:

36631

Cov.:

AF XY:

0.672

AC XY:

49971

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.906

AC:

37654

AN:

41540

American (AMR)

AF:

0.473

AC:

7220

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.629

AC:

2182

AN:

3470

East Asian (EAS)

AF:

0.453

AC:

2339

AN:

5168

South Asian (SAS)

AF:

0.738

AC:

3551

AN:

4812

European-Finnish (FIN)

AF:

0.596

AC:

6300

AN:

10568

Middle Eastern (MID)

AF:

0.650

AC:

191

AN:

294

European-Non Finnish (NFE)

AF:

0.613

AC:

41621

AN:

67952

Other (OTH)

AF:

0.631

AC:

1332

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1548

3096

4645

6193

7741

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

806

1612

2418

3224

4030

<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:

0.621

Hom.:

8738

Bravo

AF:

0.668

Asia WGS

AF:

0.624

AC:

2173

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:3

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The GSS c.275+20T>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. This variant was found in 75115/121240 control chromosomes (24686 homozygotes) in ExAC at a frequency of 0.6195563, and is present in as much as 91% in sub-populations (Africa), therefore indicating this variant is the major allele and is a benign polymorphism. In addition, at least one clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Glutathione synthetase deficiency with 5-oxoprolinuria

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glutathione synthetase deficiency without 5-oxoprolinuria

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: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

-0.91

CADD

Benign

2.3

(source)

DANN

Benign

0.55

PhyloP100

-2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over