1-109690472-C-T

Variant names:

• chr1-109690472-C-T
• rs138440339
• NM_000561.4:c.475C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_000561.4(GSTM1):​c.475C>T​(p.Leu159Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/22 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. L159V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 13)
  • Exomes 𝑓: 0.0000042 (1 hom.)
• Consequence: GSTM1 NM_000561.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0680
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3068114).

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.475C>T	p.Leu159Phe	missense	Exon 7 of 8	NP_000552.2
	GSTM1	NM_146421.3		c.456+106C>T		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.475C>T	p.Leu159Phe	missense	Exon 7 of 8	ENSP00000311469.5	P09488-1
	GSTM1	ENST00000349334.7	TSL:1	c.456+106C>T		intron	N/A	ENSP00000234981.4	P09488-2
	GSTM1	ENST00000369819.2	TSL:1	c.360+1147C>T		intron	N/A	ENSP00000358834.2	B9ZVX7

Frequencies

GnomAD3 genomes Cov.: 13

GnomAD4 exome AF: 0.00000419 AC: 3 AN: 716616 Hom.: 1 Cov.: 3 AF XY: 0.00000837 AC XY: 3 AN XY: 358418

African (AFR) AF: 0.00 AC: 0 AN: 24488

American (AMR) AF: 0.00 AC: 0 AN: 25688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13410

East Asian (EAS) AF: 0.000166 AC: 3 AN: 18046

South Asian (SAS) AF: 0.00 AC: 0 AN: 51890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2564

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 521364

Other (OTH) AF: 0.00 AC: 0 AN: 30064

GnomAD4 genome Cov.: 13

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		0.068
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.050
Sift	Benign	0.10	T
Sift4G	Benign	0.19	T
Polyphen		0.98	D
Vest4		0.44
MutPred		0.58		Loss of stability (P = 0.1328)
MVP		0.22
MPC		1.2
ClinPred		0.42	T
GERP RS		-1.4
Varity_R		0.35
gMVP		0.54
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs138440339; hg19: chr1-110233094;