chr1-109690525-C-T

Position:

• chr1-109690525-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000561.4(GSTM1):​c.528C>T​(p.Asp176=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 927,760 control chromosomes in the GnomAD database, including 51,388 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 0.27 (8706 hom., cov: 11)
  • Exomes 𝑓: 0.16 (42682 hom.)
• Consequence: GSTM1 NM_000561.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.41

Genes affected

GSTM1 (HGNC:4632): (glutathione S-transferase mu 1) 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. Null mutations of this class mu gene have been linked with an increase in a number of cancers, likely due to an increased susceptibility to environmental toxins and carcinogens. Multiple protein isoforms are encoded by transcript variants of this gene. [provided by RefSeq, Jul 2008]

GSTM2 (HGNC:4634): (glutathione S-transferase mu 2) 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP7: Synonymous conserved (PhyloP=-5.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSTM1	NM_000561.4	c.528C>T	p.Asp176=	synonymous_variant	7/8	ENST00000309851.10
GSTM1	XM_005270782.6	c.426C>T	p.Asp142=	synonymous_variant	7/8
GSTM1	NM_146421.3	c.456+159C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSTM1	ENST00000309851.10	c.528C>T	p.Asp176=	synonymous_variant	7/8	1	NM_000561.4	P1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 21363 AN: 79712 Hom.: 8692 Cov.: 11

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.339

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.181

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.290

GnomAD3 exomes AF: 0.192 AC: 33492 AN: 174206 Hom.: 12212 AF XY: 0.190 AC XY: 17998 AN XY: 94952

Gnomad AFR exome AF: 0.251

Gnomad AMR exome AF: 0.293

Gnomad ASJ exome AF: 0.0888

Gnomad EAS exome AF: 0.284

Gnomad SAS exome AF: 0.311

Gnomad FIN exome AF: 0.0745

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.165 AC: 139582 AN: 847932 Hom.: 42682 Cov.: 21 AF XY: 0.168 AC XY: 72069 AN XY: 428030

Gnomad4 AFR exome AF: 0.238

Gnomad4 AMR exome AF: 0.304

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.269

Gnomad4 SAS exome AF: 0.333

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.268 AC: 21404 AN: 79828 Hom.: 8706 Cov.: 11 AF XY: 0.266 AC XY: 10310 AN XY: 38734

Gnomad4 AFR AF: 0.322

Gnomad4 AMR AF: 0.364

Gnomad4 ASJ AF: 0.147

Gnomad4 EAS AF: 0.338

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.290

Alfa AF: 0.0861 Hom.: 768

Asia WGS AF: 0.352 AC: 690 AN: 1968

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.49
DANN	Benign	0.81

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: rs1056806; hg19: chr1-110233147; COSMIC: COSV59166436; COSMIC: COSV59166436;