6-52796249-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_145740.5(GSTA1):c.205A>G(p.Arg69Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GSTA1 NM_145740.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.13

Genes affected

GSTA1 (HGNC:4626): (glutathione S-transferase alpha 1) This gene encodes a member of a family of enzymes that function to add glutathione to target electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. This action is an important step in detoxification of these compounds. This subfamily of enzymes has a particular role in protecting cells from reactive oxygen species and the products of peroxidation. Polymorphisms in this gene influence the ability of individuals to metabolize different drugs. This gene is located in a cluster of similar genes and pseudogenes on chromosome 6. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSTA1	NM_145740.5	c.205A>G	p.Arg69Gly	missense_variant	4/7	ENST00000334575.6
GSTA1	XM_005249034.5	c.205A>G	p.Arg69Gly	missense_variant	4/6
GSTA1	NM_001319059.2	c.-8+1337A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSTA1	ENST00000334575.6	c.205A>G	p.Arg69Gly	missense_variant	4/7	1	NM_145740.5	P1
GSTA1	ENST00000476213.1	n.259A>G		non_coding_transcript_exon_variant	3/4	5
GSTA1	ENST00000493331.5	n.169+1337A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2021

The c.205A>G (p.R69G) alteration is located in exon 4 (coding exon 3) of the GSTA1 gene. This alteration results from a A to G substitution at nucleotide position 205, causing the arginine (R) at amino acid position 69 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
Cadd	Uncertain	25
Dann	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.059
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.0037	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.58	N
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Benign	0.18
Sift	Benign	0.090	T
Sift4G	Benign	0.068	T
Polyphen		0.91	P
Vest4		0.70
MutPred		0.70		Loss of MoRF binding (P = 0.0523);
MVP		0.21
MPC		0.047
ClinPred		0.98	D
GERP RS		2.7
Varity_R		0.81
gMVP		0.47

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-52661047;