6-52896853-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000847.5(GSTA3):c.622G>A(p.Ala208Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000933 in 1,614,030 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (15 hom.)
• Consequence: GSTA3 NM_000847.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -8.75

Genes affected

GSTA3 (HGNC:4628): (glutathione S-transferase alpha 3) Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. These enzymes are involved in cellular defense against toxic, carcinogenic, and pharmacologically active electrophilic compounds. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-tranferase belonging to the alpha class genes that are located in a cluster mapped to chromosome 6. Genes of the alpha class are highly related and encode enzymes with glutathione peroxidase activity. However, during evolution, this alpha class gene diverged accumulating mutations in the active site that resulted in differences in substrate specificity and catalytic activity. The enzyme encoded by this gene catalyzes the double bond isomerization of precursors for progesterone and testosterone during the biosynthesis of steroid hormones. An additional transcript variant has been identified, but its full length sequence has not been determined. [provided by RefSeq, Jul 2008]

LOC105375091 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027203262).
• BP6: Variant 6-52896853-C-T is Benign according to our data. Variant chr6-52896853-C-T is described in ClinVar as [Benign]. Clinvar id is 725541.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.001 (153/152268) while in subpopulation EAS AF= 0.0249 (129/5180). AF 95% confidence interval is 0.0214. There are 0 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSTA3	NM_000847.5	c.622G>A	p.Ala208Thr	missense_variant	7/7	ENST00000211122.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSTA3	ENST00000211122.4	c.622G>A	p.Ala208Thr	missense_variant	7/7	1	NM_000847.5	P1
GSTA3	ENST00000370968.5	c.472G>A	p.Ala158Thr	missense_variant	6/6	1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0248

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00241 AC: 607 AN: 251380 Hom.: 9 AF XY: 0.00228 AC XY: 310 AN XY: 135860

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0305

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000926 AC: 1353 AN: 1461762 Hom.: 15 Cov.: 30 AF XY: 0.000925 AC XY: 673 AN XY: 727184

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0284

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000710

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.00100 AC: 153 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74454

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0249

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00166 Hom.: 7

Bravo AF: 0.00136

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00241 AC: 292

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.0020
Dann	Benign	0.53
Eigen	Benign	-2.9
Eigen_PC	Benign	-3.0
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.018	T;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.43	N;N
REVEL	Benign	0.022
Sift	Benign	0.66	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.0	.;B
Vest4		0.040
MVP		0.055
MPC		0.034
ClinPred		0.010	T
GERP RS		-6.5
Varity_R		0.087
gMVP		0.10

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

LitVar

Other links and lift over

dbSNP: rs45620832; hg19: chr6-52761651; COSMIC: COSV52979638; COSMIC: COSV52979638;