20-34928864-C-T

Variant names:

• chr20-34928864-C-T
• rs765311167
• NM_000178.4:c.1389G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_000178.4(GSS):​c.1389G>A​(p.Ala463Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: GSS NM_000178.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.532
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 20-34928864-C-T is Benign according to our data. Variant chr20-34928864-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2860594.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.532 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSS	NM_000178.4	c.1389G>A	p.Ala463Ala	synonymous_variant	Exon 13 of 13	ENST00000651619.1	NP_000169.1
GSS	NM_001322494.1	c.1389G>A	p.Ala463Ala	synonymous_variant	Exon 13 of 13		NP_001309423.1
GSS	NM_001322495.1	c.1389G>A	p.Ala463Ala	synonymous_variant	Exon 13 of 13		NP_001309424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSS	ENST00000651619.1	c.1389G>A	p.Ala463Ala	synonymous_variant	Exon 13 of 13		NM_000178.4	ENSP00000498303.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152124 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000103 AC: 26 AN: 251318 AF XY: 0.000103

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.0000688 AC XY: 50 AN XY: 727184

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1111996

Other (OTH) AF: 0.0000662 AC: 4 AN: 60388

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152124 Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5 AN XY: 74322

African (AFR) AF: 0.0000483 AC: 2 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.0000302

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glutathione synthetase deficiency with 5-oxoprolinuria Benign:1

Feb 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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	-0.32
CADD	Benign	12
DANN	Benign	0.89
PhyloP100		-0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=91/9	polymorphism

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: rs765311167; hg19: chr20-33516667; COSMIC: COSV99404475; COSMIC: COSV99404475;