1-109689279-T-C

Variant names:

• chr1-109689279-T-C
• rs202002774
• NM_000561.4:c.314T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4 BP6_Moderate

The NM_000561.4(GSTM1):​c.314T>C​(p.Met105Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000037 (0 hom., cov: 12)
  • Exomes 𝑓: 0.0000056 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: GSTM1 NM_000561.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.66
• Publications: 3 publications found

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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3916999).
• BP6: Variant 1-109689279-T-C is Benign according to our data. Variant chr1-109689279-T-C is described in ClinVar as Benign. ClinVar VariationId is 769520.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000561.4. 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
	GSTM1	NM_000561.4	MANE Select	c.314T>C	p.Met105Thr	missense	Exon 5 of 8	NP_000552.2
	GSTM1	NM_146421.3		c.314T>C	p.Met105Thr	missense	Exon 5 of 7	NP_666533.1	X5D932

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSTM1	ENST00000309851.10	TSL:1 MANE Select	c.314T>C	p.Met105Thr	missense	Exon 5 of 8	ENSP00000311469.5	P09488-1
	GSTM1	ENST00000349334.7	TSL:1	c.314T>C	p.Met105Thr	missense	Exon 5 of 7	ENSP00000234981.4	P09488-2
	GSTM1	ENST00000369819.2	TSL:1	c.314T>C	p.Met105Thr	missense	Exon 5 of 6	ENSP00000358834.2	B9ZVX7

Frequencies

GnomAD3 genomes AF: 0.0000374 AC: 3 AN: 80224 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000187

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000152 AC: 2 AN: 131274 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000561 AC: 4 AN: 713642 Hom.: 2 Cov.: 0 AF XY: 0.00000561 AC XY: 2 AN XY: 356558

African (AFR) AF: 0.00 AC: 0 AN: 24482

American (AMR) AF: 0.00 AC: 0 AN: 24902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13394

East Asian (EAS) AF: 0.00 AC: 0 AN: 17992

South Asian (SAS) AF: 0.0000386 AC: 2 AN: 51822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2560

European-Non Finnish (NFE) AF: 0.00000385 AC: 2 AN: 519636

Other (OTH) AF: 0.00 AC: 0 AN: 29940

GnomAD4 genome AF: 0.0000373 AC: 3 AN: 80338 Hom.: 0 Cov.: 12 AF XY: 0.0000511 AC XY: 2 AN XY: 39112

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28240

American (AMR) AF: 0.000263 AC: 2 AN: 7596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1742

East Asian (EAS) AF: 0.00 AC: 0 AN: 2120

South Asian (SAS) AF: 0.00 AC: 0 AN: 2636

European-Finnish (FIN) AF: 0.000187 AC: 1 AN: 5336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 132

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 31186

Other (OTH) AF: 0.00 AC: 0 AN: 1006

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00228 Hom.: 0

ExAC AF: 0.0000601 AC: 4

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Benign	0.69
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		1.7
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.16
Sift	Benign	0.057	T
Sift4G	Benign	0.28	T
Polyphen		0.77	P
Vest4		0.41
MVP		0.22
MPC		1.2
ClinPred		0.26	T
GERP RS		2.0
Varity_R		0.75
gMVP		0.52
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs202002774; hg19: chr1-110231901;