Genetic Variant GSTM4:p.Phe178Leu (chr1-109659077-T-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000850.5(GSTM4):c.534T>A(p.Phe178Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

GSTM4
NM_000850.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.181

Publications

30 publications found

Variant links:

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]

GSTM4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.914

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GSTM4	NM_000850.5	MANE Select	c.534T>A	p.Phe178Leu	missense	Exon 7 of 8	NP_000841.1	A0A140VKE3
GSTM4	NM_147148.3		c.534T>A	p.Phe178Leu	missense	Exon 7 of 8	NP_671489.1	Q03013-2
GSTM4	NR_024538.2		n.743T>A		non_coding_transcript_exon	Exon 6 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GSTM4	ENST00000369836.9	TSL:1 MANE Select	c.534T>A	p.Phe178Leu	missense	Exon 7 of 8	ENSP00000358851.4	Q03013-1
GSTM4	ENST00000326729.9	TSL:1	c.534T>A	p.Phe178Leu	missense	Exon 7 of 8	ENSP00000316471.5	Q03013-2
GSTM4	ENST00000495742.5	TSL:1	n.590T>A		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.00089

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.027

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.14

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.0048

MetaRNN

Pathogenic

0.91

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

3.9

PhyloP100

0.18

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-4.6

REVEL

Benign

0.23

Sift

Uncertain

0.020

Sift4G

Benign

0.072

Polyphen

0.77

Vest4

0.27

MutPred

0.75

Gain of helix (P = 0.132)

MVP

0.12

MPC

0.66

ClinPred

1.0

GERP RS

-0.015

Varity_R

0.59

gMVP

0.49

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over