Genetic Variant GSS:c.-9+925A>G (chr20-34954802-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000178.4(GSS):c.-9+925A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.876 in 153,802 control chromosomes in the GnomAD database, including 59,450 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.88 ( 58908 hom., cov: 31)

Exomes 𝑓: 0.83 ( 542 hom. )

Consequence

GSS
NM_000178.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.241

Publications

11 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
GSS	NM_000178.4 link	c.-9+925A>G	intron_variant	Intron 1 of 12	ENST00000651619.1	NP_000169.1
GSS	NM_001322495.1 link	c.-95A>G	5_prime_UTR_variant	Exon 1 of 13		NP_001309424.1
GSS	NM_001322494.1 link	c.-9+1068A>G	intron_variant	Intron 1 of 12		NP_001309423.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSS	ENST00000651619.1 link	c.-9+925A>G		intron_variant	Intron 1 of 12		NM_000178.4	ENSP00000498303.1

Frequencies

GnomAD3 genomes

AF:

0.877

AC:

133339

AN:

152114

Hom.:

58842

Cov.:

show subpopulations

Gnomad AFR

AF:

0.969

Gnomad AMI

AF:

0.735

Gnomad AMR

AF:

0.879

Gnomad ASJ

AF:

0.749

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.959

Gnomad FIN

AF:

0.838

Gnomad MID

AF:

0.785

Gnomad NFE

AF:

0.821

Gnomad OTH

AF:

0.842

GnomAD4 exome

AF:

0.831

AC:

1304

AN:

1570

Hom.:

542

Cov.:

AF XY:

0.831

AC XY:

680

AN XY:

818

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

1.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.830

AC:

1276

AN:

1538

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.750

AC:

AN:

Other (OTH)

AF:

1.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<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:

0.877

AC:

133465

AN:

152232

Hom.:

58908

Cov.:

AF XY:

0.879

AC XY:

65451

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.969

AC:

40252

AN:

41554

American (AMR)

AF:

0.879

AC:

13438

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.749

AC:

2602

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5169

AN:

5176

South Asian (SAS)

AF:

0.958

AC:

4625

AN:

4826

European-Finnish (FIN)

AF:

0.838

AC:

8874

AN:

10594

Middle Eastern (MID)

AF:

0.793

AC:

233

AN:

294

European-Non Finnish (NFE)

AF:

0.821

AC:

55824

AN:

68008

Other (OTH)

AF:

0.843

AC:

1778

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

815

1630

2444

3259

4074

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

896

1792

2688

3584

4480

<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:

0.863

Hom.:

53180

Bravo

AF:

0.881

Asia WGS

AF:

0.974

AC:

3387

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

6.7

(source)

DANN

Benign

0.84

PhyloP100

-0.24

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

Computational scores

Splicing

Publications

Other links and lift over