20-34945933-A-C

Variant names:

• chr20-34945933-A-C
• rs734111
• NM_000178.4:c.275+20T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000178.4(GSS):​c.275+20T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 1,611,838 control chromosomes in the GnomAD database, including 323,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (36631 hom., cov: 33)
  • Exomes 𝑓: 0.62 (286520 hom.)
• Consequence: GSS NM_000178.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.60
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 20-34945933-A-C is Benign according to our data. Variant chr20-34945933-A-C is described in ClinVar as Benign. ClinVar VariationId is 255474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 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.275+20T>G		intron	N/A	NP_000169.1
	GSS	NM_001322494.1		c.275+20T>G		intron	N/A	NP_001309423.1
	GSS	NM_001322495.1		c.275+20T>G		intron	N/A	NP_001309424.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSS	ENST00000651619.1	MANE Select	c.275+20T>G		intron	N/A	ENSP00000498303.1
	GSS	ENST00000451957.2	TSL:1	c.275+20T>G		intron	N/A	ENSP00000407517.2
	GSS	ENST00000854976.1		c.275+20T>G		intron	N/A	ENSP00000525035.1

Frequencies

GnomAD3 genomes AF: 0.676 AC: 102712 AN: 151970 Hom.: 36571 Cov.: 33

Gnomad AFR AF: 0.906

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.740

Gnomad FIN AF: 0.596

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.627

GnomAD2 exomes AF: 0.600 AC: 150741 AN: 251084 AF XY: 0.612

Gnomad AFR exome AF: 0.919

Gnomad AMR exome AF: 0.307

Gnomad ASJ exome AF: 0.636

Gnomad EAS exome AF: 0.484

Gnomad FIN exome AF: 0.608

Gnomad NFE exome AF: 0.620

Gnomad OTH exome AF: 0.592

GnomAD4 exome AF: 0.621 AC: 905987 AN: 1459750 Hom.: 286520 Cov.: 35 AF XY: 0.624 AC XY: 453408 AN XY: 726278

African (AFR) AF: 0.921 AC: 30800 AN: 33442

American (AMR) AF: 0.326 AC: 14555 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.637 AC: 16629 AN: 26108

East Asian (EAS) AF: 0.443 AC: 17573 AN: 39678

South Asian (SAS) AF: 0.742 AC: 63930 AN: 86168

European-Finnish (FIN) AF: 0.604 AC: 32197 AN: 53264

Middle Eastern (MID) AF: 0.641 AC: 3674 AN: 5728

European-Non Finnish (NFE) AF: 0.620 AC: 688463 AN: 1110334

Other (OTH) AF: 0.633 AC: 38166 AN: 60314

GnomAD4 genome AF: 0.676 AC: 102813 AN: 152088 Hom.: 36631 Cov.: 33 AF XY: 0.672 AC XY: 49971 AN XY: 74324

African (AFR) AF: 0.906 AC: 37654 AN: 41540

American (AMR) AF: 0.473 AC: 7220 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 2182 AN: 3470

East Asian (EAS) AF: 0.453 AC: 2339 AN: 5168

South Asian (SAS) AF: 0.738 AC: 3551 AN: 4812

European-Finnish (FIN) AF: 0.596 AC: 6300 AN: 10568

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.613 AC: 41621 AN: 67952

Other (OTH) AF: 0.631 AC: 1332 AN: 2110

Alfa AF: 0.621 Hom.: 8738

Bravo AF: 0.668

Asia WGS AF: 0.624 AC: 2173 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Glutathione synthetase deficiency with 5-oxoprolinuria (2)
-	-	1	Glutathione synthetase deficiency without 5-oxoprolinuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.3
DANN	Benign	0.55
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs734111; hg19: chr20-33533736; COSMIC: COSV53811989; COSMIC: COSV53811989;