1-109669374-G-A

Variant summary

Our verdict is Benign. Variant got -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 donor 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. 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_donor_region, intron
• Scores: Splicing: ADA: 0.0006587
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.71

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 Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 45 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSTM2	NM_000848.4	c.259+3G>A		splice_donor_region_variant, intron_variant		ENST00000241337.9
GSTM2	NM_001142368.2	c.259+3G>A		splice_donor_region_variant, intron_variant
GSTM2	XR_007059236.1	n.318+3G>A		splice_donor_region_variant, intron_variant, non_coding_transcript_variant
GSTM2	XR_007059237.1	n.318+3G>A		splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSTM2	ENST00000241337.9	c.259+3G>A		splice_donor_region_variant, intron_variant		1	NM_000848.4	P1

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

GnomAD3 exomes AF: 0.00340 AC: 856 AN: 251494 Hom.: 16 AF XY: 0.00258 AC XY: 350 AN XY: 135920

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 SAS exome AF: 0.000196

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

Gnomad4 AFR exome AF: 0.0515

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00318

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

Gnomad4 AFR AF: 0.0484

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00770 Hom.: 15

Bravo AF: 0.0158

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 23, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	17
Dann	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs58615559; hg19: chr1-110211996; COSMIC: COSV53984501; COSMIC: COSV53984501;