chr20-34928759-C-A

Variant names:

• chr20-34928759-C-A
• rs200882573
• NM_000178.4:c.*69G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000178.4(GSS):​c.*69G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000921 in 1,564,530 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00090 (2 hom.)
• Consequence: GSS NM_000178.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.207
• Publications: 1 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=-0.81).
• BP6: Variant 20-34928759-C-A is Benign according to our data. Variant chr20-34928759-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 338291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00108 (164/152244) while in subpopulation AMR AF = 0.00353 (54/15298). AF 95% confidence interval is 0.00278. There are 1 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSS	NM_000178.4	c.*69G>T		3_prime_UTR_variant	Exon 13 of 13	ENST00000651619.1	NP_000169.1
GSS	NM_001322494.1	c.*69G>T		3_prime_UTR_variant	Exon 13 of 13		NP_001309423.1
GSS	NM_001322495.1	c.*69G>T		3_prime_UTR_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.*69G>T		3_prime_UTR_variant	Exon 13 of 13		NM_000178.4	ENSP00000498303.1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152126 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00384

GnomAD4 exome AF: 0.000904 AC: 1277 AN: 1412286 Hom.: 2 Cov.: 25 AF XY: 0.000894 AC XY: 630 AN XY: 704942

African (AFR) AF: 0.000184 AC: 6 AN: 32566

American (AMR) AF: 0.00118 AC: 52 AN: 44244

Ashkenazi Jewish (ASJ) AF: 0.000622 AC: 16 AN: 25738

East Asian (EAS) AF: 0.00 AC: 0 AN: 39386

South Asian (SAS) AF: 0.000754 AC: 64 AN: 84848

European-Finnish (FIN) AF: 0.000188 AC: 10 AN: 53214

Middle Eastern (MID) AF: 0.00354 AC: 20 AN: 5656

European-Non Finnish (NFE) AF: 0.000977 AC: 1043 AN: 1067946

Other (OTH) AF: 0.00112 AC: 66 AN: 58688

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152244 Hom.: 1 Cov.: 31 AF XY: 0.00105 AC XY: 78 AN XY: 74430

African (AFR) AF: 0.000337 AC: 14 AN: 41534

American (AMR) AF: 0.00353 AC: 54 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68026

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.00146

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inherited glutathione synthetase deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.2
DANN	Benign	0.69
PhyloP100		0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs200882573; hg19: chr20-33516562;