rs7483

Positions:

• chr1-109737079-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000849.5(GSTM3):​c.670G>A​(p.Val224Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 1,599,424 control chromosomes in the GnomAD database, including 87,787 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.27 (6899 hom., cov: 33)
  • Exomes 𝑓: 0.32 (80888 hom.)
• Consequence: GSTM3 NM_000849.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.69

Genes affected

GSTM3 (HGNC:4635): (glutathione S-transferase mu 3) Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. 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-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are organized in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic. These genetic variations can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Mutations of this class mu gene have been linked with a slight increase in a number of cancers, likely due to exposure with environmental toxins. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2008]

(HGNC:):

GSTM5 (HGNC:4637): (glutathione S-transferase mu 5) Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. 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-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are organized in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic. These genetic variations can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Diversification of these genes has occurred in regions encoding substrate-binding domains, as well as in tissue expression patterns, to accommodate an increasing number of foreign compounds. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3028056E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSTM3	NM_000849.5	c.670G>A	p.Val224Ile	missense_variant	9/9	ENST00000361066.7	NP_000840.2
GSTM3	NR_024537.2	n.904G>A		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSTM3	ENST00000361066.7	c.670G>A	p.Val224Ile	missense_variant	9/9	1	NM_000849.5	ENSP00000354357	P1
	ENST00000431955.1	n.565C>T		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40816 AN: 152046 Hom.: 6894 Cov.: 33

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.745

Gnomad SAS AF: 0.422

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.276

GnomAD3 exomes AF: 0.351 AC: 88166 AN: 251354 Hom.: 17966 AF XY: 0.353 AC XY: 47928 AN XY: 135854

Gnomad AFR exome AF: 0.0965

Gnomad AMR exome AF: 0.443

Gnomad ASJ exome AF: 0.264

Gnomad EAS exome AF: 0.740

Gnomad SAS exome AF: 0.426

Gnomad FIN exome AF: 0.295

Gnomad NFE exome AF: 0.296

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.320 AC: 463717 AN: 1447260 Hom.: 80888 Cov.: 29 AF XY: 0.324 AC XY: 233676 AN XY: 720904

Gnomad4 AFR exome AF: 0.0876

Gnomad4 AMR exome AF: 0.432

Gnomad4 ASJ exome AF: 0.263

Gnomad4 EAS exome AF: 0.754

Gnomad4 SAS exome AF: 0.427

Gnomad4 FIN exome AF: 0.300

Gnomad4 NFE exome AF: 0.301

Gnomad4 OTH exome AF: 0.321

GnomAD4 genome AF: 0.268 AC: 40843 AN: 152164 Hom.: 6899 Cov.: 33 AF XY: 0.272 AC XY: 20206 AN XY: 74388

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.338

Gnomad4 ASJ AF: 0.268

Gnomad4 EAS AF: 0.744

Gnomad4 SAS AF: 0.423

Gnomad4 FIN AF: 0.288

Gnomad4 NFE AF: 0.304

Gnomad4 OTH AF: 0.281

Alfa AF: 0.305 Hom.: 19758

Bravo AF: 0.266

TwinsUK AF: 0.290 AC: 1077

ALSPAC AF: 0.311 AC: 1197

ESP6500AA AF: 0.112 AC: 493

ESP6500EA AF: 0.297 AC: 2550

ExAC AF: 0.341 AC: 41448

Asia WGS AF: 0.504 AC: 1752 AN: 3478

EpiCase AF: 0.295

EpiControl AF: 0.287

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.0070
DANN	Benign	0.52
DEOGEN2	Benign	0.038	T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.29	T;.
MetaRNN	Benign	0.0000023	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.84	N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.010	N;N
REVEL	Benign	0.0090
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.015
ClinPred		0.00030	T
GERP RS		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.18

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: rs7483; hg19: chr1-110279701; COSMIC: COSV56661922; COSMIC: COSV56661922;