NM_000178.4:c.129+528C>G

Variant names:

• chr20-34951196-G-C
• rs6060127
• NM_000178.4:c.129+528C>G

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+528C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 152,092 control chromosomes in the GnomAD database, including 5,175 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 0.25 (5175 hom., cov: 33)
• Consequence: GSS NM_000178.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.111
• Publications: 8 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=-0.67).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.304 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+528C>G		intron	N/A	NP_000169.1	P48637-1
	GSS	NM_001322494.1		c.129+528C>G		intron	N/A	NP_001309423.1	V9HWJ1
	GSS	NM_001322495.1		c.129+528C>G		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+528C>G		intron	N/A	ENSP00000498303.1	P48637-1
	GSS	ENST00000451957.2	TSL:1	c.129+528C>G		intron	N/A	ENSP00000407517.2	P48637-2
	GSS	ENST00000854976.1		c.129+528C>G		intron	N/A	ENSP00000525035.1

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38061 AN: 151974 Hom.: 5176 Cov.: 33

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.234

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

GnomAD4 genome AF: 0.250 AC: 38066 AN: 152092 Hom.: 5175 Cov.: 33 AF XY: 0.246 AC XY: 18316 AN XY: 74334

African (AFR) AF: 0.185 AC: 7664 AN: 41494

American (AMR) AF: 0.189 AC: 2889 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 718 AN: 3470

East Asian (EAS) AF: 0.226 AC: 1171 AN: 5178

South Asian (SAS) AF: 0.302 AC: 1455 AN: 4818

European-Finnish (FIN) AF: 0.244 AC: 2572 AN: 10556

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.308 AC: 20929 AN: 67974

Other (OTH) AF: 0.231 AC: 488 AN: 2110

Alfa AF: 0.275 Hom.: 737

Bravo AF: 0.238

Asia WGS AF: 0.235 AC: 820 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.87
PhyloP100		-0.11
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: rs6060127; hg19: chr20-33538999;