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_001322495.1(GSS):c.-95A>G variant causes a 5 prime UTR 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_001322495.1 5_prime_UTR

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322495.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GSS	NM_000178.4	MANE Select	c.-9+925A>G	intron	N/A	NP_000169.1	P48637-1
GSS	NM_001322495.1		c.-95A>G	5_prime_UTR	Exon 1 of 13	NP_001309424.1	P48637-1
GSS	NM_001322494.1		c.-9+1068A>G	intron	N/A	NP_001309423.1	V9HWJ1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GSS	ENST00000651619.1	MANE Select	c.-9+925A>G	intron	N/A	ENSP00000498303.1	P48637-1
GSS	ENST00000644793.1		c.-95A>G	5_prime_UTR	Exon 1 of 13	ENSP00000495750.1	P48637-1
GSS	ENST00000854976.1		c.-9+925A>G	intron	N/A	ENSP00000525035.1

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 v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over