6-52984579-A-G

Position:

• chr6-52984579-A-G

Variant summary

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

The NM_001512.4(GSTA4):​c.299T>C​(p.Leu100Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,613,716 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: GSTA4 NM_001512.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.319

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=0.017355025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSTA4	NM_001512.4	c.299T>C	p.Leu100Pro	missense_variant	5/7	ENST00000370963.9	NP_001503.1
GSTA4	XM_005249035.5	c.299T>C	p.Leu100Pro	missense_variant	5/7		XP_005249092.1
GSTA4	XM_011514534.4	c.188T>C	p.Leu63Pro	missense_variant	4/6		XP_011512836.1
GSTA4	XM_011514535.4	c.188T>C	p.Leu63Pro	missense_variant	4/6		XP_011512837.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSTA4	ENST00000370963.9	c.299T>C	p.Leu100Pro	missense_variant	5/7	1	NM_001512.4	ENSP00000360002	P1

Frequencies

GnomAD3 genomes AF: 0.000979 AC: 149 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00100 AC: 252 AN: 251308 Hom.: 0 AF XY: 0.00104 AC XY: 141 AN XY: 135838

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00123 AC: 1804 AN: 1461438 Hom.: 1 Cov.: 31 AF XY: 0.00123 AC XY: 892 AN XY: 727070

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.00145

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.000978 AC: 149 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000913 AC XY: 68 AN XY: 74452

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00171

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.00101

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000914 AC: 111

EpiCase AF: 0.00174

EpiControl AF: 0.00166

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;T;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.91	.;D;T;D
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.017	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.25	T;T;T;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.98	D;.;D;.
Vest4		0.57
MVP		0.34
MPC		0.72
ClinPred		0.027	T
GERP RS		5.0
Varity_R		0.74

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: rs45551133; hg19: chr6-52849377;