chr20-34935066-T-C

Variant names:

• chr20-34935066-T-C
• rs6119545
• NM_000178.4:c.834+510A>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.834+510A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 152,014 control chromosomes in the GnomAD database, including 23,043 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 0.54 (23043 hom., cov: 31)
• Consequence: GSS NM_000178.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.890
• Publications: 7 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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.713 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSS	NM_000178.4	MANE Select	c.834+510A>G		intron	N/A	NP_000169.1
	GSS	NM_001322494.1		c.834+510A>G		intron	N/A	NP_001309423.1
	GSS	NM_001322495.1		c.834+510A>G		intron	N/A	NP_001309424.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSS	ENST00000651619.1	MANE Select	c.834+510A>G		intron	N/A	ENSP00000498303.1
	GSS	ENST00000451957.2	TSL:1	c.501+510A>G		intron	N/A	ENSP00000407517.2
	GSS	ENST00000643188.1		c.834+510A>G		intron	N/A	ENSP00000493903.1

Frequencies

GnomAD3 genomes AF: 0.542 AC: 82342 AN: 151896 Hom.: 23035 Cov.: 31

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.461

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.735

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.534

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

GnomAD4 genome AF: 0.542 AC: 82352 AN: 152014 Hom.: 23043 Cov.: 31 AF XY: 0.541 AC XY: 40196 AN XY: 74290

African (AFR) AF: 0.442 AC: 18303 AN: 41456

American (AMR) AF: 0.422 AC: 6443 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2158 AN: 3470

East Asian (EAS) AF: 0.450 AC: 2328 AN: 5176

South Asian (SAS) AF: 0.733 AC: 3530 AN: 4814

European-Finnish (FIN) AF: 0.594 AC: 6267 AN: 10544

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.612 AC: 41591 AN: 67974

Other (OTH) AF: 0.538 AC: 1134 AN: 2106

Alfa AF: 0.578 Hom.: 3352

Bravo AF: 0.517

Asia WGS AF: 0.591 AC: 2058 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.5
DANN	Benign	0.55
PhyloP100		0.89
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: rs6119545; hg19: chr20-33522869;