1-109662396-G-C

Variant names:

• chr1-109662396-G-C
• rs521999
• ENST00000326729.9:c.568-2615G>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_147148.3(GSTM4):​c.568-2615G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 152,120 control chromosomes in the GnomAD database, including 1,229 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.12 (1229 hom., cov: 32)
• Consequence: GSTM4 NM_147148.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00

Genes affected

GSTM4 (HGNC:4636): (glutathione S-transferase mu 4) 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. Diversification of these genes has occurred in regions encoding substrate-binding domains, as well as in tissue expression patterns, to accommodate an increasing number of foreign compounds. Multiple transcript variants, each encoding a distinct protein isoform, have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSTM4	NM_147148.3	c.568-2615G>C		intron_variant	Intron 7 of 7		NP_671489.1
GSTM4	XR_007059238.1	n.859-2615G>C		intron_variant	Intron 7 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GSTM4	ENST00000326729.9	c.568-2615G>C		intron_variant	Intron 7 of 7	1		ENSP00000316471.5

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18544 AN: 152002 Hom.: 1218 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.0890

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0563

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.116

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.122 AC: 18581 AN: 152120 Hom.: 1229 Cov.: 32 AF XY: 0.119 AC XY: 8813 AN XY: 74370

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.0889

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0565

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.114

Alfa AF: 0.0576 Hom.: 58

Bravo AF: 0.122

Asia WGS AF: 0.0400 AC: 141 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.42
DANN	Benign	0.54

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs521999; hg19: chr1-110205018; COSMIC: COSV58694056; COSMIC: COSV58694056;