NM_000178.4:c.1301+190T>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000178.4(GSS):​c.1301+190T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 698,280 control chromosomes in the GnomAD database, including 140,808 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (35085 hom., cov: 31)
  • Exomes 𝑓: 0.61 (105723 hom.)
• Consequence: GSS NM_000178.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.439554E-4).
• BP6: Variant 20-34929211-A-G is Benign according to our data. Variant chr20-34929211-A-G is described in ClinVar as Benign. ClinVar VariationId is 1232487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.857 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.1301+190T>C		intron	N/A	NP_000169.1
	GSS	NM_001322494.1		c.1301+190T>C		intron	N/A	NP_001309423.1
	GSS	NM_001322495.1		c.1301+190T>C		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>C		intron	N/A	ENSP00000498303.1
	GSS	ENST00000451957.2	TSL:1	c.968+190T>C		intron	N/A	ENSP00000407517.2
	GSS	ENST00000642498.1		c.1328T>C	p.Leu443Ser	missense	Exon 13 of 13	ENSP00000493631.1

Frequencies

GnomAD3 genomes AF: 0.665 AC: 100956 AN: 151888 Hom.: 35060 Cov.: 31

Gnomad AFR AF: 0.865

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.632

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.740

Gnomad FIN AF: 0.595

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.614

Gnomad OTH AF: 0.623

GnomAD4 exome AF: 0.613 AC: 334922 AN: 546274 Hom.: 105723 Cov.: 6 AF XY: 0.621 AC XY: 181328 AN XY: 291858

African (AFR) AF: 0.866 AC: 13101 AN: 15130

American (AMR) AF: 0.343 AC: 10467 AN: 30560

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 11007 AN: 17230

East Asian (EAS) AF: 0.435 AC: 13917 AN: 31962

South Asian (SAS) AF: 0.740 AC: 41736 AN: 56374

European-Finnish (FIN) AF: 0.601 AC: 20565 AN: 34218

Middle Eastern (MID) AF: 0.632 AC: 1446 AN: 2288

European-Non Finnish (NFE) AF: 0.621 AC: 204184 AN: 328772

Other (OTH) AF: 0.622 AC: 18499 AN: 29740

GnomAD4 genome AF: 0.664 AC: 101007 AN: 152006 Hom.: 35085 Cov.: 31 AF XY: 0.661 AC XY: 49064 AN XY: 74282

African (AFR) AF: 0.864 AC: 35839 AN: 41474

American (AMR) AF: 0.469 AC: 7160 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 2189 AN: 3466

East Asian (EAS) AF: 0.451 AC: 2324 AN: 5156

South Asian (SAS) AF: 0.738 AC: 3555 AN: 4814

European-Finnish (FIN) AF: 0.595 AC: 6295 AN: 10572

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.614 AC: 41706 AN: 67938

Other (OTH) AF: 0.627 AC: 1326 AN: 2116

Alfa AF: 0.613 Hom.: 12491

Bravo AF: 0.655

TwinsUK AF: 0.611 AC: 2264

ALSPAC AF: 0.606 AC: 2335

ESP6500AA AF: 0.865 AC: 1197

ESP6500EA AF: 0.622 AC: 1978

Asia WGS AF: 0.619 AC: 2155 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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
AlphaMissense	Benign	0.085
BayesDel_noAF	Benign	-0.89
CADD	Benign	12
DANN	Benign	0.78
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.00074	T
PhyloP100		0.59
GERP RS		0.40
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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; COSMIC: COSV53627208; COSMIC: COSV53627208;