rs560018

Positions:

• chr1-109657738-T-C

Variant summary

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

The NM_000850.5(GSTM4):​c.260-34T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 1,613,966 control chromosomes in the GnomAD database, including 90,313 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (6109 hom., cov: 32)
  • Exomes 𝑓: 0.33 (84204 hom.)
• Consequence: GSTM4 NM_000850.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.30

Genes affected

GSTM4 (HGNC:4636): (glutathione S-transferase mu 4) 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. Multiple transcript variants, each encoding a distinct protein isoform, have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSTM4	NM_000850.5	c.260-34T>C		intron_variant		ENST00000369836.9	NP_000841.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSTM4	ENST00000369836.9	c.260-34T>C		intron_variant		1	NM_000850.5	ENSP00000358851	P1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39595 AN: 152024 Hom.: 6109 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.0464

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.268

GnomAD3 exomes AF: 0.265 AC: 66638 AN: 251444 Hom.: 10317 AF XY: 0.269 AC XY: 36495 AN XY: 135886

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.325

Gnomad EAS exome AF: 0.0496

Gnomad SAS exome AF: 0.158

Gnomad FIN exome AF: 0.283

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.328 AC: 479180 AN: 1461824 Hom.: 84204 Cov.: 37 AF XY: 0.324 AC XY: 235381 AN XY: 727212

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.207

Gnomad4 ASJ exome AF: 0.324

Gnomad4 EAS exome AF: 0.0335

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.290

Gnomad4 NFE exome AF: 0.367

Gnomad4 OTH exome AF: 0.297

GnomAD4 genome AF: 0.260 AC: 39595 AN: 152142 Hom.: 6109 Cov.: 32 AF XY: 0.254 AC XY: 18872 AN XY: 74386

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.327

Gnomad4 EAS AF: 0.0459

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.364

Gnomad4 OTH AF: 0.265

Alfa AF: 0.335 Hom.: 12773

Bravo AF: 0.254

Asia WGS AF: 0.0950 AC: 333 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.1
DANN	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs560018; hg19: chr1-110200360; COSMIC: COSV58694494; COSMIC: COSV58694494;