rs7265992

Variant names:

• chr20-34937604-G-A
• rs7265992
• NM_000178.4:c.609-581C>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.609-581C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 152,078 control chromosomes in the GnomAD database, including 1,979 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 0.15 (1979 hom., cov: 32)
• Consequence: GSS NM_000178.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.500
• Publications: 16 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSS	NM_000178.4	c.609-581C>T		intron_variant	Intron 6 of 12	ENST00000651619.1	NP_000169.1
GSS	NM_001322494.1	c.609-581C>T		intron_variant	Intron 6 of 12		NP_001309423.1
GSS	NM_001322495.1	c.609-581C>T		intron_variant	Intron 6 of 12		NP_001309424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSS	ENST00000651619.1	c.609-581C>T		intron_variant	Intron 6 of 12		NM_000178.4	ENSP00000498303.1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23416 AN: 151960 Hom.: 1980 Cov.: 32

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0910

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.136

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

GnomAD4 genome AF: 0.154 AC: 23414 AN: 152078 Hom.: 1979 Cov.: 32 AF XY: 0.152 AC XY: 11330 AN XY: 74334

African (AFR) AF: 0.157 AC: 6519 AN: 41470

American (AMR) AF: 0.0908 AC: 1388 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 425 AN: 3466

East Asian (EAS) AF: 0.229 AC: 1185 AN: 5176

South Asian (SAS) AF: 0.300 AC: 1444 AN: 4808

European-Finnish (FIN) AF: 0.117 AC: 1236 AN: 10576

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10853 AN: 67982

Other (OTH) AF: 0.135 AC: 285 AN: 2110

Alfa AF: 0.136 Hom.: 400

Bravo AF: 0.147

Asia WGS AF: 0.236 AC: 825 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.62
DANN	Benign	0.49
PhyloP100		-0.50
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: rs7265992; hg19: chr20-33525407;