NM_000850.5:c.575A>G

Variant names:

• chr1-109661172-A-G
• rs931232559
• NM_000850.5:c.575A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000850.5(GSTM4):​c.575A>G​(p.Glu192Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GSTM4 NM_000850.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90
• Publications: 0 publications found

Genes affected

GSTM4 (HGNC:4636): (glutathione S-transferase mu 4) 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. Diversification of these genes has occurred in regions encoding substrate-binding domains, as well as in tissue expression patterns, to accommodate an increasing number of foreign compounds. Multiple transcript variants, each encoding a distinct protein isoform, have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000850.5. 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
	GSTM4	NM_000850.5	MANE Select	c.575A>G	p.Glu192Gly	missense	Exon 8 of 8	NP_000841.1	A0A140VKE3
	GSTM4	NM_147148.3		c.567+2062A>G		intron	N/A	NP_671489.1	Q03013-2
	GSTM4	NR_024538.2		n.784A>G		non_coding_transcript_exon	Exon 7 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSTM4	ENST00000369836.9	TSL:1 MANE Select	c.575A>G	p.Glu192Gly	missense	Exon 8 of 8	ENSP00000358851.4	Q03013-1
	GSTM4	ENST00000326729.9	TSL:1	c.567+2062A>G		intron	N/A	ENSP00000316471.5	Q03013-2
	GSTM4	ENST00000495742.5	TSL:1	n.631A>G		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251332 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461108 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726864

African (AFR) AF: 0.00 AC: 0 AN: 33158

American (AMR) AF: 0.0000895 AC: 4 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111672

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

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	0.079
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.038
Eigen_PC	Benign	0.0046
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.9
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.19
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.012	D
Polyphen		0.0030	B
Vest4		0.17
MutPred		0.60		Gain of MoRF binding (P = 0.046)
MVP		0.26
MPC		0.44
ClinPred		0.88	D
GERP RS		2.6
Varity_R		0.44
gMVP		0.27
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.32		Position offset: -7

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

Other links and lift over

dbSNP: rs931232559; hg19: chr1-110203794;