1-109668143-A-T

Position:

• chr1-109668143-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000848.4(GSTM2):​c.28A>T​(p.Ile10Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,486 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: 0.0000089 (0 hom.)
• Consequence: GSTM2 NM_000848.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.38

Genes affected

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2993818).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSTM2	NM_000848.4	c.28A>T	p.Ile10Phe	missense_variant	1/8	ENST00000241337.9
GSTM2	NM_001142368.2	c.28A>T	p.Ile10Phe	missense_variant	1/9
GSTM2	XR_007059236.1	n.87A>T		non_coding_transcript_exon_variant	1/7
GSTM2	XR_007059237.1	n.87A>T		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSTM2	ENST00000241337.9	c.28A>T	p.Ile10Phe	missense_variant	1/8	1	NM_000848.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461486 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727082

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Nov 17, 2022

The c.28A>T (p.I10F) alteration is located in exon 1 (coding exon 1) of the GSTM2 gene. This alteration results from a A to T substitution at nucleotide position 28, causing the isoleucine (I) at amino acid position 10 to be replaced by a phenylalanine (F). 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	0.72
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.012	.;T;T;.;T;T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.097	N
LIST_S2	Uncertain	0.88	D;D;D;.;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.30	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.;.;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PROVEAN	Uncertain	-3.0	D;D;.;D;D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.029	D;D;.;D;D;D;D
Sift4G	Benign	0.065	T;T;T;T;T;T;T
Polyphen		0.40	.;.;.;.;B;.;.
Vest4		0.27
MutPred		0.66		Gain of methylation at R11 (P = 0.0442);Gain of methylation at R11 (P = 0.0442);Gain of methylation at R11 (P = 0.0442);Gain of methylation at R11 (P = 0.0442);Gain of methylation at R11 (P = 0.0442);Gain of methylation at R11 (P = 0.0442);Gain of methylation at R11 (P = 0.0442);
MVP		0.12
MPC		1.6
ClinPred		0.94	D
GERP RS		-0.97
Varity_R		0.66
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1647399362; hg19: chr1-110210765;