rs549546640

Variant names:

• chr20-34928865-G-A
• rs549546640
• NM_000178.4:c.1388C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000178.4(GSS):​c.1388C>T​(p.Ala463Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000539 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A463A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: GSS NM_000178.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.50
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSS	NM_000178.4	MANE Select	c.1388C>T	p.Ala463Val	missense	Exon 13 of 13	NP_000169.1
	GSS	NM_001322494.1		c.1388C>T	p.Ala463Val	missense	Exon 13 of 13	NP_001309423.1
	GSS	NM_001322495.1		c.1388C>T	p.Ala463Val	missense	Exon 13 of 13	NP_001309424.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSS	ENST00000651619.1	MANE Select	c.1388C>T	p.Ala463Val	missense	Exon 13 of 13	ENSP00000498303.1
	GSS	ENST00000451957.2	TSL:1	c.1055C>T	p.Ala352Val	missense	Exon 9 of 9	ENSP00000407517.2
	GSS	ENST00000854976.1		c.1442C>T	p.Ala481Val	missense	Exon 13 of 13	ENSP00000525035.1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000796 AC: 20 AN: 251294 AF XY: 0.0000736

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461746 Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23 AN XY: 727162

African (AFR) AF: 0.000807 AC: 27 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111972

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74428

African (AFR) AF: 0.000891 AC: 37 AN: 41506

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000383 Hom.: 0

Bravo AF: 0.000321

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.95	P
Vest4		0.45
MVP		0.92
MPC		0.32
ClinPred		0.20	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.67
gMVP		0.93
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs549546640; hg19: chr20-33516668;