1-109687893-A-G

Position:

• chr1-109687893-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP3_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07

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

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	UniProt
GSTM1	NM_000561.4	c.20A>G	p.Tyr7Cys	missense_variant	1/8	ENST00000309851.10
GSTM1	NM_146421.3	c.20A>G	p.Tyr7Cys	missense_variant	1/7
GSTM1	XM_005270782.6	c.-136A>G		5_prime_UTR_variant	1/8

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000241 AC: 2 AN: 82854 Hom.: 1 Cov.: 13

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: 2 AN: 711406 Hom.: 1 Cov.: 4 AF XY: 0.00000562 AC XY: 2 AN XY: 355670

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: 2 AN: 82854 Hom.: 1 Cov.: 13 AF XY: 0.0000494 AC XY: 2 AN XY: 40456

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

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	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;T;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.0075	T
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Pathogenic	4.8	H;.;H;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
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	D
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

Other links and lift over

dbSNP: rs1173098385; hg19: chr1-110230515;