6-52987360-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001512.4(GSTA4):c.136G>A(p.Asp46Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,433,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GSTA4 NM_001512.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0230

Genes affected

GSTA4 (HGNC:4629): (glutathione S-transferase alpha 4) 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. The alpha class genes, which are located in a cluster on chromosome 6, are highly related and encode enzymes with glutathione peroxidase activity that function in the detoxification of lipid peroxidation products. Reactive electrophiles produced by oxidative metabolism have been linked to a number of degenerative diseases including Parkinson's disease, Alzheimer's disease, cataract formation, and atherosclerosis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.023657948).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSTA4	NM_001512.4	c.136G>A	p.Asp46Asn	missense_variant	3/7	ENST00000370963.9
GSTA4	XM_005249035.5	c.136G>A	p.Asp46Asn	missense_variant	3/7
GSTA4	XM_011514534.4	c.29-1777G>A		intron_variant
GSTA4	XM_011514535.4	c.29-1777G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSTA4	ENST00000370963.9	c.136G>A	p.Asp46Asn	missense_variant	3/7	1	NM_001512.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1433364 Hom.: 0 Cov.: 25 AF XY: 0.00000140 AC XY: 1 AN XY: 714384

Gnomad4 AFR exome AF: 0.00

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: 9.17e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Oct 26, 2022

The c.136G>A (p.D46N) alteration is located in exon 3 (coding exon 2) of the GSTA4 gene. This alteration results from a G to A substitution at nucleotide position 136, causing the aspartic acid (D) at amino acid position 46 to be replaced by an asparagine (N). 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	Benign	0.089
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	15
Dann	Benign	0.36
DEOGEN2	Benign	0.065	T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.33	N
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.024	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.67	N;N
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.96	N;N
REVEL	Benign	0.046
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.21
MutPred		0.33		Gain of ubiquitination at K43 (P = 0.078);Gain of ubiquitination at K43 (P = 0.078);
MVP		0.15
MPC		0.12
ClinPred		0.15	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr6-52852158; COSMIC: COSV63955253;