20-34951780-G-C

Position:

• chr20-34951780-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000178.4(GSS):​c.73C>G​(p.Arg25Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: GSS NM_000178.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.643

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3329103).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSS	NM_000178.4	c.73C>G	p.Arg25Gly	missense_variant	2/13	ENST00000651619.1	NP_000169.1
GSS	NM_001322494.1	c.73C>G	p.Arg25Gly	missense_variant	2/13		NP_001309423.1
GSS	NM_001322495.1	c.73C>G	p.Arg25Gly	missense_variant	2/13		NP_001309424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSS	ENST00000651619.1	c.73C>G	p.Arg25Gly	missense_variant	2/13		NM_000178.4	ENSP00000498303	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inherited glutathione synthetase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2021

This sequence change replaces arginine with glycine at codon 25 of the GSS protein (p.Arg25Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with GSS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	.;D;.;D;D;.;.;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.0011
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.87	.;.;D;.;D;D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.4	L;L;.;L;L;L;.;.;.
MutationTaster	Benign	0.79	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.63	.;N;.;.;.;N;.;.;.
REVEL	Uncertain	0.55
Sift	Benign	0.30	.;T;.;.;.;T;.;.;.
Sift4G	Benign	0.31	.;T;.;.;.;T;.;.;.
Polyphen		0.29	.;B;.;B;B;.;.;.;.
Vest4		0.52, 0.50
MutPred		0.64		Loss of methylation at R25 (P = 0.0617);Loss of methylation at R25 (P = 0.0617);Loss of methylation at R25 (P = 0.0617);Loss of methylation at R25 (P = 0.0617);Loss of methylation at R25 (P = 0.0617);Loss of methylation at R25 (P = 0.0617);Loss of methylation at R25 (P = 0.0617);Loss of methylation at R25 (P = 0.0617);Loss of methylation at R25 (P = 0.0617);
MVP		0.84
MPC		0.41
ClinPred		0.22	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs930264754; hg19: chr20-33539583;