20-34929211-A-C

Variant names:

• chr20-34929211-A-C
• rs1801310
• NM_000178.4:c.1301+190T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000178.4(GSS):​c.1301+190T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GSS NM_000178.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.588
• Publications: 8 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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.1301+190T>G		intron	N/A	NP_000169.1
	GSS	NM_001322494.1		c.1301+190T>G		intron	N/A	NP_001309423.1
	GSS	NM_001322495.1		c.1301+190T>G		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.1301+190T>G		intron	N/A	ENSP00000498303.1
	GSS	ENST00000451957.2	TSL:1	c.968+190T>G		intron	N/A	ENSP00000407517.2
	GSS	ENST00000642498.1		c.1328T>G	p.Leu443*	stop_gained	Exon 13 of 13	ENSP00000493631.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 546604 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 292022

African (AFR) AF: 0.00 AC: 0 AN: 15132

American (AMR) AF: 0.00 AC: 0 AN: 30578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17240

East Asian (EAS) AF: 0.00 AC: 0 AN: 31964

South Asian (SAS) AF: 0.00 AC: 0 AN: 56408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 329006

Other (OTH) AF: 0.00 AC: 0 AN: 29746

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 12491

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	13
DANN	Benign	0.76
FATHMM_MKL	Benign	0.11	N
PhyloP100		0.59
GERP RS		0.40
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1801310; hg19: chr20-33517014;