NM_001512.4:c.136G>A

Variant names:

• chr6-52987360-C-T
• NM_001512.4:c.136G>A

Variant summary

Our verdict is Likely benign. The variant received -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. 16/21 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
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001512.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSTA4	NM_001512.4	MANE Select	c.136G>A	p.Asp46Asn	missense	Exon 3 of 7	NP_001503.1	O15217-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSTA4	ENST00000370963.9	TSL:1 MANE Select	c.136G>A	p.Asp46Asn	missense	Exon 3 of 7	ENSP00000360002.4	O15217-1
	GSTA4	ENST00000370959.1	TSL:5	c.136G>A	p.Asp46Asn	missense	Exon 3 of 7	ENSP00000359998.1	O15217-1
	GSTA4	ENST00000887782.1		c.136G>A	p.Asp46Asn	missense	Exon 3 of 7	ENSP00000557841.1

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

African (AFR) AF: 0.00 AC: 0 AN: 32612

American (AMR) AF: 0.00 AC: 0 AN: 42920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25730

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 83500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090538

Other (OTH) AF: 0.00 AC: 0 AN: 59488

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.67	N
PhyloP100		-0.023
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.96	N
REVEL	Benign	0.046
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.33		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
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

hg19: chr6-52852158; COSMIC: COSV63955253;