rs2273684

Variant names:

• chr20-34941963-T-G
• rs2273684
• NM_000178.4:c.492-134A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000178.4(GSS):​c.492-134A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 724,288 control chromosomes in the GnomAD database, including 80,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.51 (21260 hom., cov: 31)
  • Exomes 𝑓: 0.45 (59638 hom.)
• Consequence: GSS NM_000178.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.53
• Publications: 41 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 20-34941963-T-G is Benign according to our data. Variant chr20-34941963-T-G is described in ClinVar as Benign. ClinVar VariationId is 1224925.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSS	NM_000178.4	c.492-134A>C		intron_variant	Intron 5 of 12	ENST00000651619.1	NP_000169.1
GSS	NM_001322494.1	c.492-134A>C		intron_variant	Intron 5 of 12		NP_001309423.1
GSS	NM_001322495.1	c.492-134A>C		intron_variant	Intron 5 of 12		NP_001309424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSS	ENST00000651619.1	c.492-134A>C		intron_variant	Intron 5 of 12		NM_000178.4	ENSP00000498303.1

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77595 AN: 151814 Hom.: 21236 Cov.: 31

Gnomad AFR AF: 0.708

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.478

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.484

GnomAD4 exome AF: 0.445 AC: 254943 AN: 572356 Hom.: 59638 AF XY: 0.447 AC XY: 139999 AN XY: 312902

African (AFR) AF: 0.711 AC: 11847 AN: 16664

American (AMR) AF: 0.259 AC: 10321 AN: 39786

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 10143 AN: 19504

East Asian (EAS) AF: 0.225 AC: 7526 AN: 33396

South Asian (SAS) AF: 0.447 AC: 29737 AN: 66600

European-Finnish (FIN) AF: 0.490 AC: 19218 AN: 39212

Middle Eastern (MID) AF: 0.483 AC: 1124 AN: 2326

European-Non Finnish (NFE) AF: 0.465 AC: 150817 AN: 324364

Other (OTH) AF: 0.466 AC: 14210 AN: 30504

GnomAD4 genome AF: 0.511 AC: 77648 AN: 151932 Hom.: 21260 Cov.: 31 AF XY: 0.508 AC XY: 37730 AN XY: 74252

African (AFR) AF: 0.707 AC: 29292 AN: 41422

American (AMR) AF: 0.379 AC: 5777 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 1757 AN: 3472

East Asian (EAS) AF: 0.224 AC: 1153 AN: 5146

South Asian (SAS) AF: 0.435 AC: 2093 AN: 4812

European-Finnish (FIN) AF: 0.478 AC: 5051 AN: 10560

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30960 AN: 67944

Other (OTH) AF: 0.490 AC: 1034 AN: 2112

Alfa AF: 0.468 Hom.: 35789

Bravo AF: 0.510

Asia WGS AF: 0.380 AC: 1322 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.30
DANN	Benign	0.78
PhyloP100		-1.5
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: rs2273684; hg19: chr20-33529766;