1-109690516-G-C

Position:

• chr1-109690516-G-C

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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 (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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSTM1	NM_000561.4	c.519G>C	p.Lys173Asn	missense_variant	7/8	ENST00000309851.10	NP_000552.2
GSTM1	XM_005270782.6	c.417G>C	p.Lys139Asn	missense_variant	7/8		XP_005270839.1
GSTM1	NM_146421.3	c.456+150G>C		intron_variant			NP_666533.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSTM1	ENST00000309851.10	c.519G>C	p.Lys173Asn	missense_variant	7/8	1	NM_000561.4	ENSP00000311469	P1

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

GnomAD3 exomes AF: 0.362 AC: 52343 AN: 144724 Hom.: 21395 AF XY: 0.356 AC XY: 27753 AN XY: 77924

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 SAS exome AF: 0.219

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

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.477

Gnomad4 ASJ exome AF: 0.398

Gnomad4 EAS exome AF: 0.704

Gnomad4 SAS exome AF: 0.229

Gnomad4 FIN exome AF: 0.462

Gnomad4 NFE exome AF: 0.393

Gnomad4 OTH exome AF: 0.353

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

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.351

Gnomad4 ASJ AF: 0.392

Gnomad4 EAS AF: 0.649

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.412

Gnomad4 NFE AF: 0.349

Gnomad4 OTH AF: 0.303

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 v4.3

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;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.25	T;T
MetaRNN	Benign	0.0000038	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.074
Sift	Benign	0.15	T;T
Sift4G	Benign	0.31	T;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

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

Publications

LitVar

Other links and lift over

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