20-34928846-G-T

Position:

• chr20-34928846-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_Moderate PM2 PP3_Strong

The NM_000178.4(GSS):​c.1407C>A​(p.Asp469Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000015 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: GSS NM_000178.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.67

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 Likely_pathogenic. Variant got 8 ACMG points.

• PS1: Transcript NM_000178.4 (GSS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSS	NM_000178.4	c.1407C>A	p.Asp469Glu	missense_variant	13/13	ENST00000651619.1
GSS	NM_001322494.1	c.1407C>A	p.Asp469Glu	missense_variant	13/13
GSS	NM_001322495.1	c.1407C>A	p.Asp469Glu	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSS	ENST00000651619.1	c.1407C>A	p.Asp469Glu	missense_variant	13/13		NM_000178.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251370 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461800 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000468 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 19, 2023

Variant summary: GSS c.1407C>A (p.Asp469Glu) results in a conservative amino acid change to a highly conserved residue (HGMD) in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251370 control chromosomes (gnomAD). c.1407C>A has been reported in the literature in an individual affected with severe Glutathione Synthetase Deficiency (Dahl_1997), and they were reported as compound heterozygous with another variant that may be pathogenic. These data suggest the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 9215686). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 04, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;D;D;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	.;.;.;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.8	.;H;H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.7	.;D;.;.;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0030	.;D;.;.;D
Sift4G	Uncertain	0.0050	.;D;.;.;D
Polyphen		1.0	.;D;D;D;.
Vest4		0.94, 0.99
MutPred		0.95		.;Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;
MVP		0.96
MPC		0.77
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.95
gMVP		0.97

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: rs1419704426; hg19: chr20-33516649;