chr1-109669374-G-A

Variant names:

• chr1-109669374-G-A
• rs58615559
• NM_000848.4:c.259+3G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000848.4(GSTM2):​c.259+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,614,222 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (45 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (50 hom.)
• Consequence: GSTM2 NM_000848.4 splice_region, intron
• Scores: Splicing: ADA: 0.0006587
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.71
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 1-109669374-G-A is Benign according to our data. Variant chr1-109669374-G-A is described in ClinVar as Benign. ClinVar VariationId is 775572.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0139 (2112/152336) while in subpopulation AFR AF = 0.0484 (2012/41568). AF 95% confidence interval is 0.0466. There are 45 homozygotes in GnomAd4. There are 1004 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000848.4. 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
	GSTM2	NM_000848.4	MANE Select	c.259+3G>A		splice_region intron	N/A	NP_000839.1	P28161-1
	GSTM2	NM_001142368.2		c.259+3G>A		splice_region intron	N/A	NP_001135840.1	P28161-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSTM2	ENST00000241337.9	TSL:1 MANE Select	c.259+3G>A		splice_region intron	N/A	ENSP00000241337.4	P28161-1
	GSTM2	ENST00000414179.6	TSL:1	c.-54+3G>A		splice_region intron	N/A	ENSP00000404662.2	E9PGV1
	GSTM2	ENST00000864527.1		c.532+3G>A		splice_region intron	N/A	ENSP00000534586.1

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2109 AN: 152218 Hom.: 45 Cov.: 31

Gnomad AFR AF: 0.0484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00340 AC: 856 AN: 251494 AF XY: 0.00258

Gnomad AFR exome AF: 0.0481

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00141 AC: 2061 AN: 1461886 Hom.: 50 Cov.: 33 AF XY: 0.00118 AC XY: 861 AN XY: 727244

African (AFR) AF: 0.0515 AC: 1724 AN: 33474

American (AMR) AF: 0.00192 AC: 86 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1112012

Other (OTH) AF: 0.00318 AC: 192 AN: 60396

GnomAD4 genome AF: 0.0139 AC: 2112 AN: 152336 Hom.: 45 Cov.: 31 AF XY: 0.0135 AC XY: 1004 AN XY: 74494

African (AFR) AF: 0.0484 AC: 2012 AN: 41568

American (AMR) AF: 0.00497 AC: 76 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68030

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00702 Hom.: 17

Bravo AF: 0.0158

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.73
PhyloP100		2.7
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00066
dbscSNV1_RF	Benign	0.028
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: rs58615559; hg19: chr1-110211996; COSMIC: COSV53984501; COSMIC: COSV53984501;