20-34928846-G-T

Variant names:

• chr20-34928846-G-T
• rs1419704426
• NM_000178.4:c.1407C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000178.4(GSS):​c.1407C>A​(p.Asp469Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000015 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: GSS NM_000178.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.67
• Publications: 3 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

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.1407C>A	p.Asp469Glu	missense	Exon 13 of 13	NP_000169.1	P48637-1
	GSS	NM_001322494.1		c.1407C>A	p.Asp469Glu	missense	Exon 13 of 13	NP_001309423.1	V9HWJ1
	GSS	NM_001322495.1		c.1407C>A	p.Asp469Glu	missense	Exon 13 of 13	NP_001309424.1	P48637-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSS	ENST00000651619.1	MANE Select	c.1407C>A	p.Asp469Glu	missense	Exon 13 of 13	ENSP00000498303.1	P48637-1
	GSS	ENST00000451957.2	TSL:1	c.1074C>A	p.Asp358Glu	missense	Exon 9 of 9	ENSP00000407517.2	P48637-2
	GSS	ENST00000854976.1		c.1461C>A	p.Asp487Glu	missense	Exon 13 of 13	ENSP00000525035.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251370 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461800 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000468 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		3.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.95		Gain of loop (P = 0.1069)
MVP		0.96
MPC		0.77
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.95
gMVP		0.97
Mutation Taster		=2/98	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: rs1419704426; hg19: chr20-33516649;