dbSNP rs2236270: GSS:c.834+224C>A (chr20-34935352-G-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.20

Publications

27 publications found

Variant links:

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)

GSS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
GSS	NM_000178.4 link	c.834+224C>A	intron_variant	Intron 9 of 12	ENST00000651619.1	NP_000169.1
GSS	NM_001322494.1 link	c.834+224C>A	intron_variant	Intron 9 of 12		NP_001309423.1
GSS	NM_001322495.1 link	c.834+224C>A	intron_variant	Intron 9 of 12		NP_001309424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSS	ENST00000651619.1 link	c.834+224C>A		intron_variant	Intron 9 of 12		NM_000178.4	ENSP00000498303.1

Frequencies

GnomAD3 genomes

AF:

0.328

AC:

49799

AN:

151936

Hom.:

8684

Cov.:

show subpopulations

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.:

AF XY:

0.327

AC XY:

24293

AN XY:

74334

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1693

3386

5078

6771

8464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

510

1020

1530

2040

2550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over