1-109690516-G-C

Variant names:

• chr1-109690516-G-C
• rs1065411
• NM_000561.4:c.519G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000561.4(GSTM1):​c.519G>C​(p.Lys173Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. K173R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.27 (9154 hom., cov: 11)
  • Exomes 𝑓: 0.38 (111272 hom.)
• Consequence: GSTM1 NM_000561.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0570
• Publications: 51 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.7616996E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000561.4. 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
	GSTM1	NM_000561.4	MANE Select	c.519G>C	p.Lys173Asn	missense	Exon 7 of 8	NP_000552.2
	GSTM1	NM_146421.3		c.456+150G>C		intron	N/A	NP_666533.1	X5D932

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSTM1	ENST00000309851.10	TSL:1 MANE Select	c.519G>C	p.Lys173Asn	missense	Exon 7 of 8	ENSP00000311469.5	P09488-1
	GSTM1	ENST00000349334.7	TSL:1	c.456+150G>C		intron	N/A	ENSP00000234981.4	P09488-2
	GSTM1	ENST00000369819.2	TSL:1	c.360+1191G>C		intron	N/A	ENSP00000358834.2	B9ZVX7

Frequencies

GnomAD3 genomes AF: 0.268 AC: 21474 AN: 80058 Hom.: 9146 Cov.: 11

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0785

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.647

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.300

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.304

GnomAD2 exomes AF: 0.362 AC: 52343 AN: 144724 AF XY: 0.356

Gnomad AFR exome AF: 0.0981

Gnomad AMR exome AF: 0.474

Gnomad ASJ exome AF: 0.368

Gnomad EAS exome AF: 0.645

Gnomad FIN exome AF: 0.438

Gnomad NFE exome AF: 0.368

Gnomad OTH exome AF: 0.365

GnomAD4 exome AF: 0.384 AC: 265781 AN: 692526 Hom.: 111272 Cov.: 14 AF XY: 0.378 AC XY: 132236 AN XY: 349856

African (AFR) AF: 0.104 AC: 2578 AN: 24740

American (AMR) AF: 0.477 AC: 13110 AN: 27484

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 5602 AN: 14064

East Asian (EAS) AF: 0.704 AC: 13455 AN: 19110

South Asian (SAS) AF: 0.229 AC: 11796 AN: 51538

European-Finnish (FIN) AF: 0.462 AC: 14081 AN: 30478

Middle Eastern (MID) AF: 0.290 AC: 756 AN: 2604

European-Non Finnish (NFE) AF: 0.393 AC: 194024 AN: 493100

Other (OTH) AF: 0.353 AC: 10379 AN: 29408

GnomAD4 genome AF: 0.268 AC: 21499 AN: 80176 Hom.: 9154 Cov.: 11 AF XY: 0.270 AC XY: 10495 AN XY: 38888

African (AFR) AF: 0.101 AC: 2860 AN: 28356

American (AMR) AF: 0.351 AC: 2638 AN: 7510

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 687 AN: 1752

East Asian (EAS) AF: 0.649 AC: 1379 AN: 2124

South Asian (SAS) AF: 0.211 AC: 562 AN: 2658

European-Finnish (FIN) AF: 0.412 AC: 2125 AN: 5154

Middle Eastern (MID) AF: 0.265 AC: 35 AN: 132

European-Non Finnish (NFE) AF: 0.349 AC: 10873 AN: 31114

Other (OTH) AF: 0.303 AC: 313 AN: 1032

Alfa AF: 0.328 Hom.: 803

ESP6500AA AF: 0.119 AC: 495

ESP6500EA AF: 0.396 AC: 2632

ExAC AF: 0.468 AC: 50024

Asia WGS AF: 0.352 AC: 689 AN: 1964

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	11
DANN	Benign	0.86
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0000038	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		-0.057
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.074
Sift	Benign	0.15	T
Sift4G	Benign	0.31	T
Polyphen		0.028	B
Vest4		0.082
MutPred		0.11		Loss of methylation at K173 (P = 0.0027)
MPC		1.2
ClinPred		0.010	T
GERP RS		-1.1
Varity_R		0.33
gMVP		0.71
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

dbSNP: rs1065411; hg19: chr1-110233138; COSMIC: COSV59166453; COSMIC: COSV59166453;