dbSNP rs2025096: GSS:c.-8-337C>T (chr20-34952197-G-A) – 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.-8-337C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 374,418 control chromosomes in the GnomAD database, including 7,926 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 0.19 ( 2841 hom., cov: 33)

Exomes 𝑓: 0.21 ( 5085 hom. )

Consequence

GSS
NM_000178.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0560

Publications

19 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

new If you want to explore the variant's impact on the transcript NM_000178.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.79).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000178.4. 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.-8-337C>T	intron	N/A	NP_000169.1	P48637-1
GSS	NM_001322494.1		c.-8-337C>T	intron	N/A	NP_001309423.1	V9HWJ1
GSS	NM_001322495.1		c.-8-337C>T	intron	N/A	NP_001309424.1	P48637-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GSS	ENST00000651619.1	MANE Select	c.-8-337C>T	intron	N/A	ENSP00000498303.1	P48637-1
GSS	ENST00000645102.1		c.-54C>T	5_prime_UTR	Exon 1 of 4	ENSP00000495829.1	A0A2R8Y790
GSS	ENST00000854976.1		c.-8-337C>T	intron	N/A	ENSP00000525035.1

Frequencies

GnomAD3 genomes

AF:

0.190

AC:

28904

AN:

152042

Hom.:

2838

Cov.:

show subpopulations

Gnomad AFR

AF:

0.172

Gnomad AMI

AF:

0.241

Gnomad AMR

AF:

0.160

Gnomad ASJ

AF:

0.301

Gnomad EAS

AF:

0.140

Gnomad SAS

AF:

0.270

Gnomad FIN

AF:

0.205

Gnomad MID

AF:

0.306

Gnomad NFE

AF:

0.196

Gnomad OTH

AF:

0.200

GnomAD4 exome

AF:

0.208

AC:

46306

AN:

222256

Hom.:

5085

Cov.:

AF XY:

0.214

AC XY:

25563

AN XY:

119234

show subpopulations

African (AFR)

AF:

0.177

AC:

1163

AN:

6570

American (AMR)

AF:

0.139

AC:

1610

AN:

11554

Ashkenazi Jewish (ASJ)

AF:

0.312

AC:

1821

AN:

5842

East Asian (EAS)

AF:

0.144

AC:

1513

AN:

10520

South Asian (SAS)

AF:

0.260

AC:

10120

AN:

38954

European-Finnish (FIN)

AF:

0.211

AC:

2065

AN:

9782

Middle Eastern (MID)

AF:

0.310

AC:

248

AN:

800

European-Non Finnish (NFE)

AF:

0.200

AC:

25360

AN:

126678

Other (OTH)

AF:

0.208

AC:

2406

AN:

11556

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1717

3434

5150

6867

8584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

198

396

594

792

990

<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:

0.190

AC:

28912

AN:

152162

Hom.:

2841

Cov.:

AF XY:

0.190

AC XY:

14156

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.172

AC:

7137

AN:

41526

American (AMR)

AF:

0.159

AC:

2435

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.301

AC:

1043

AN:

3470

East Asian (EAS)

AF:

0.140

AC:

725

AN:

5178

South Asian (SAS)

AF:

0.270

AC:

1299

AN:

4814

European-Finnish (FIN)

AF:

0.205

AC:

2170

AN:

10594

Middle Eastern (MID)

AF:

0.323

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.196

AC:

13356

AN:

67986

Other (OTH)

AF:

0.205

AC:

433

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1228

2456

3683

4911

6139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

322

644

966

1288

1610

<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:

0.185

Hom.:

589

Bravo

AF:

0.186

Asia WGS

AF:

0.221

AC:

770

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.4

(source)

DANN

Benign

0.72

PhyloP100

-0.056

PromoterAI

0.011

Neutral

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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