Genetic Variant NM_000178.4: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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GSS	NM_000178.4 link	c.-8-337C>T	intron_variant	Intron 1 of 12	ENST00000651619.1	NP_000169.1	P48637-1V9HWJ1
GSS	NM_001322494.1 link	c.-8-337C>T	intron_variant	Intron 1 of 12		NP_001309423.1	P48637-1V9HWJ1
GSS	NM_001322495.1 link	c.-8-337C>T	intron_variant	Intron 1 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.-8-337C>T		intron_variant	Intron 1 of 12		NM_000178.4	ENSP00000498303.1		P48637-1

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 v4.3

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

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