Variant chr1-109687893-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_000561.4(GSTM1):c.20A>G(p.Tyr7Cys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000024 ( 1 hom., cov: 13)

Exomes 𝑓: 0.0000028 ( 1 hom. )

Consequence

GSTM1
NM_000561.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.07

Variant links:

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]

GSTM1 links:

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]

GSTM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a mutagenesis_site Reduces catalytic activity 100-fold. (size 0) in uniprot entity GSTM1_HUMAN

PP3

MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GSTM1	NM_000561.4 linkuse as main transcript	c.20A>G	p.Tyr7Cys	missense_variant	1/8	ENST00000309851.10
GSTM1	NM_146421.3 linkuse as main transcript	c.20A>G	p.Tyr7Cys	missense_variant	1/7
GSTM1	XM_005270782.6 linkuse as main transcript	c.-136A>G		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSTM1	ENST00000309851.10 linkuse as main transcript	c.20A>G	p.Tyr7Cys	missense_variant	1/8	1	NM_000561.4	P1	P09488-1

Frequencies

GnomAD3 genomes

AF:

0.0000241

AC:

AN:

82854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000630

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000281

AC:

AN:

711406

Hom.:

Cov.:

AF XY:

0.00000562

AC XY:

AN XY:

355670

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000386

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000241

AC:

AN:

82854

Hom.:

Cov.:

AF XY:

0.0000494

AC XY:

AN XY:

40456

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000630

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2023

The c.20A>G (p.Y7C) alteration is located in exon 1 (coding exon 1) of the GSTM1 gene. This alteration results from a A to G substitution at nucleotide position 20, causing the tyrosine (Y) at amino acid position 7 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

T;T;.;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Benign

0.0075

MetaRNN

Pathogenic

0.87

D;D;D;D;D

MetaSVM

Benign

-0.98

MutationAssessor

Pathogenic

4.8

H;.;H;.;.

MutationTaster

Benign

0.99

D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.2

D;D;D;D;D

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;.;D;.;.

Vest4

0.70

MutPred

0.80

Gain of catalytic residue at W8 (P = 0.0034);Gain of catalytic residue at W8 (P = 0.0034);Gain of catalytic residue at W8 (P = 0.0034);Gain of catalytic residue at W8 (P = 0.0034);Gain of catalytic residue at W8 (P = 0.0034);

MVP

0.40

MPC

2.4

ClinPred

1.0

GERP RS

1.9

Varity_R

0.97

gMVP

0.98

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over