rs6060124

Variant names:

• chr20-34949094-C-A
• rs6060124
• NM_000178.4:c.129+2630G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000178.4(GSS):​c.129+2630G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 151,896 control chromosomes in the GnomAD database, including 5,864 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 0.27 (5864 hom., cov: 32)
• Consequence: GSS NM_000178.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.840
• Publications: 17 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.301 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSS	NM_000178.4	MANE Select	c.129+2630G>T		intron	N/A	NP_000169.1	P48637-1
	GSS	NM_001322494.1		c.129+2630G>T		intron	N/A	NP_001309423.1	V9HWJ1
	GSS	NM_001322495.1		c.129+2630G>T		intron	N/A	NP_001309424.1	P48637-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSS	ENST00000651619.1	MANE Select	c.129+2630G>T		intron	N/A	ENSP00000498303.1	P48637-1
	GSS	ENST00000451957.2	TSL:1	c.129+2630G>T		intron	N/A	ENSP00000407517.2	P48637-2
	GSS	ENST00000854976.1		c.129+2630G>T		intron	N/A	ENSP00000525035.1

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41070 AN: 151778 Hom.: 5863 Cov.: 32

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.238

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.270 AC: 41084 AN: 151896 Hom.: 5864 Cov.: 32 AF XY: 0.266 AC XY: 19776 AN XY: 74236

African (AFR) AF: 0.306 AC: 12653 AN: 41396

American (AMR) AF: 0.187 AC: 2863 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 704 AN: 3472

East Asian (EAS) AF: 0.228 AC: 1177 AN: 5164

South Asian (SAS) AF: 0.302 AC: 1455 AN: 4810

European-Finnish (FIN) AF: 0.224 AC: 2359 AN: 10542

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19207 AN: 67924

Other (OTH) AF: 0.235 AC: 496 AN: 2112

Alfa AF: 0.267 Hom.: 9875

Bravo AF: 0.264

Asia WGS AF: 0.246 AC: 859 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.3
DANN	Benign	0.44
PhyloP100		-0.84
Mutation Taster		=100/0	polymorphism (auto)

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: rs6060124; hg19: chr20-33536897;