chr20-34928738-T-C

Variant names:

• chr20-34928738-T-C
• rs35747685
• NM_000178.4:c.*90A>G

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.*90A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,445,878 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (8 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (8 hom.)
• Consequence: GSS NM_000178.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.643
• Publications: 2 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 20-34928738-T-C is Benign according to our data. Variant chr20-34928738-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 338290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00514 (782/152026) while in subpopulation AFR AF = 0.018 (746/41438). AF 95% confidence interval is 0.0169. There are 8 homozygotes in GnomAd4. There are 372 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSS	NM_000178.4	c.*90A>G		3_prime_UTR_variant	Exon 13 of 13	ENST00000651619.1	NP_000169.1
GSS	NM_001322494.1	c.*90A>G		3_prime_UTR_variant	Exon 13 of 13		NP_001309423.1
GSS	NM_001322495.1	c.*90A>G		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.*90A>G		3_prime_UTR_variant	Exon 13 of 13		NM_000178.4	ENSP00000498303.1

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 781 AN: 151908 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.000729 AC: 943 AN: 1293852 Hom.: 8 Cov.: 19 AF XY: 0.000612 AC XY: 398 AN XY: 650448

African (AFR) AF: 0.0184 AC: 555 AN: 30218

American (AMR) AF: 0.000642 AC: 27 AN: 42058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24802

East Asian (EAS) AF: 0.00 AC: 0 AN: 38374

South Asian (SAS) AF: 0.0000246 AC: 2 AN: 81268

European-Finnish (FIN) AF: 0.000134 AC: 7 AN: 52388

Middle Eastern (MID) AF: 0.000186 AC: 1 AN: 5382

European-Non Finnish (NFE) AF: 0.000312 AC: 301 AN: 964592

Other (OTH) AF: 0.000913 AC: 50 AN: 54770

GnomAD4 genome AF: 0.00514 AC: 782 AN: 152026 Hom.: 8 Cov.: 31 AF XY: 0.00501 AC XY: 372 AN XY: 74304

African (AFR) AF: 0.0180 AC: 746 AN: 41438

American (AMR) AF: 0.00157 AC: 24 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67974

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00147 Hom.: 1

Bravo AF: 0.00563

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Dec 01, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Inherited glutathione synthetase deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.71
DANN	Benign	0.55
PhyloP100		-0.64
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: rs35747685; hg19: chr20-33516541;