20-34935352-G-T

Variant names:

• chr20-34935352-G-T
• rs2236270
• NM_000178.4:c.834+224C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000178.4(GSS):​c.834+224C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 152,052 control chromosomes in the GnomAD database, including 8,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.33 (8685 hom., cov: 32)
• Consequence: GSS NM_000178.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.20
• Publications: 27 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 20-34935352-G-T is Benign according to our data. Variant chr20-34935352-G-T is described in ClinVar as Benign. ClinVar VariationId is 1181524.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000178.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSS	NM_000178.4	MANE Select	c.834+224C>A		intron	N/A	NP_000169.1
	GSS	NM_001322494.1		c.834+224C>A		intron	N/A	NP_001309423.1
	GSS	NM_001322495.1		c.834+224C>A		intron	N/A	NP_001309424.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSS	ENST00000651619.1	MANE Select	c.834+224C>A		intron	N/A	ENSP00000498303.1
	GSS	ENST00000451957.2	TSL:1	c.501+224C>A		intron	N/A	ENSP00000407517.2
	GSS	ENST00000643188.1		c.834+224C>A		intron	N/A	ENSP00000493903.1

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49799 AN: 151936 Hom.: 8684 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.340

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.328 AC: 49804 AN: 152052 Hom.: 8685 Cov.: 32 AF XY: 0.327 AC XY: 24293 AN XY: 74334

African (AFR) AF: 0.241 AC: 9988 AN: 41500

American (AMR) AF: 0.285 AC: 4343 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 1456 AN: 3468

East Asian (EAS) AF: 0.142 AC: 733 AN: 5166

South Asian (SAS) AF: 0.365 AC: 1761 AN: 4824

European-Finnish (FIN) AF: 0.391 AC: 4126 AN: 10558

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26218 AN: 67960

Other (OTH) AF: 0.344 AC: 727 AN: 2114

Alfa AF: 0.368 Hom.: 13252

Bravo AF: 0.314

Asia WGS AF: 0.266 AC: 929 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.81
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs2236270; hg19: chr20-33523155; COSMIC: COSV53814752; COSMIC: COSV53814752;