chr1-109690515-A-G

Variant names:

• chr1-109690515-A-G
• rs769295127
• NM_000561.4:c.518A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000561.4(GSTM1):​c.518A>G​(p.Lys173Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 12)
  • Exomes 𝑓: 0.000026 (9 hom.)
  • Failed GnomAD Quality Control
• Consequence: GSTM1 NM_000561.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.04
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

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.518A>G	p.Lys173Arg	missense	Exon 7 of 8	NP_000552.2
	GSTM1	NM_146421.3		c.456+149A>G		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.518A>G	p.Lys173Arg	missense	Exon 7 of 8	ENSP00000311469.5	P09488-1
	GSTM1	ENST00000349334.7	TSL:1	c.456+149A>G		intron	N/A	ENSP00000234981.4	P09488-2
	GSTM1	ENST00000369819.2	TSL:1	c.360+1190A>G		intron	N/A	ENSP00000358834.2	B9ZVX7

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD2 exomes AF: 0.0000851 AC: 13 AN: 152792 AF XY: 0.0000607

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00145

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000262 AC: 20 AN: 762244 Hom.: 9 Cov.: 14 AF XY: 0.0000287 AC XY: 11 AN XY: 382998

African (AFR) AF: 0.00 AC: 0 AN: 26528

American (AMR) AF: 0.00 AC: 0 AN: 27984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14684

East Asian (EAS) AF: 0.000933 AC: 18 AN: 19286

South Asian (SAS) AF: 0.00 AC: 0 AN: 53424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 554986

Other (OTH) AF: 0.0000630 AC: 2 AN: 31744

GnomAD4 genome Cov.: 12

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000531 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.44
DANN	Benign	0.86
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-1.0
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.027
Sift	Benign	0.13	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.070
MutPred		0.26		Loss of methylation at K173 (P = 0.0045)
MVP		0.31
MPC		0.83
ClinPred		0.065	T
GERP RS		-7.1
Varity_R		0.26
gMVP		0.48
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs769295127; hg19: chr1-110233137;