1-165632229-G-A

Variant names:

• chr1-165632229-G-A
• rs9333378
• NM_004528.4:c.-8+936G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PVS1_Moderate BA1

The ENST00000367885.5(MGST3):​c.-9-2G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 1,610,452 control chromosomes in the GnomAD database, including 318,698 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as association (no stars).

• Frequency:
  • Genomes: 𝑓 0.58 (26822 hom., cov: 32)
  • Exomes 𝑓: 0.63 (291876 hom.)
• Consequence: MGST3 ENST00000367885.5 splice_acceptor, intron
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: -0.147
• Publications: 22 publications found

Genes affected

MGST3 (HGNC:7064): (microsomal glutathione S-transferase 3) This gene encodes a member of the MAPEG (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism) protein family. Members of this family are involved in the production of leukotrienes and prostaglandin E, important mediators of inflammation. This gene encodes an enzyme which catalyzes the conjugation of leukotriene A4 and reduced glutathione to produce leukotriene C4. This enzyme also demonstrates glutathione-dependent peroxidase activity towards lipid hydroperoxides.[provided by RefSeq, May 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08782435 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9, offset of 0 (no position change), new splice context is: aactttaattccttccctAGgga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.948 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000367885.5. 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
	MGST3	NM_004528.4	MANE Select	c.-8+936G>A		intron	N/A	NP_004519.1	O14880

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MGST3	ENST00000367889.8	TSL:1 MANE Select	c.-8+936G>A		intron	N/A	ENSP00000356864.3	O14880
	MGST3	ENST00000367883.3	TSL:3	c.-9-2G>A		splice_acceptor intron	N/A	ENSP00000356858.1	Q5VV89
	MGST3	ENST00000367885.5	TSL:2	c.-9-2G>A		splice_acceptor intron	N/A	ENSP00000356860.1	Q5VV89

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87662 AN: 151994 Hom.: 26802 Cov.: 32

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.739

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.970

Gnomad SAS AF: 0.794

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.611

Gnomad OTH AF: 0.614

GnomAD2 exomes AF: 0.673 AC: 162575 AN: 241404 AF XY: 0.677

Gnomad AFR exome AF: 0.365

Gnomad AMR exome AF: 0.752

Gnomad ASJ exome AF: 0.736

Gnomad EAS exome AF: 0.975

Gnomad FIN exome AF: 0.628

Gnomad NFE exome AF: 0.616

Gnomad OTH exome AF: 0.653

GnomAD4 exome AF: 0.626 AC: 913255 AN: 1458340 Hom.: 291876 Cov.: 36 AF XY: 0.632 AC XY: 458347 AN XY: 725536

African (AFR) AF: 0.356 AC: 11919 AN: 33446

American (AMR) AF: 0.744 AC: 33275 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 19061 AN: 26118

East Asian (EAS) AF: 0.978 AC: 38809 AN: 39696

South Asian (SAS) AF: 0.770 AC: 66406 AN: 86186

European-Finnish (FIN) AF: 0.622 AC: 32526 AN: 52264

Middle Eastern (MID) AF: 0.666 AC: 3823 AN: 5740

European-Non Finnish (NFE) AF: 0.603 AC: 669010 AN: 1109894

Other (OTH) AF: 0.637 AC: 38426 AN: 60284

GnomAD4 genome AF: 0.577 AC: 87711 AN: 152112 Hom.: 26822 Cov.: 32 AF XY: 0.586 AC XY: 43540 AN XY: 74362

African (AFR) AF: 0.377 AC: 15650 AN: 41476

American (AMR) AF: 0.672 AC: 10281 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 2561 AN: 3472

East Asian (EAS) AF: 0.970 AC: 5026 AN: 5180

South Asian (SAS) AF: 0.794 AC: 3833 AN: 4826

European-Finnish (FIN) AF: 0.630 AC: 6666 AN: 10582

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.611 AC: 41524 AN: 67966

Other (OTH) AF: 0.618 AC: 1305 AN: 2110

Alfa AF: 0.605 Hom.: 60848

Bravo AF: 0.572

Asia WGS AF: 0.836 AC: 2909 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: association

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Pulmonary disease, chronic obstructive, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	9.3
DANN	Benign	0.78
PhyloP100		-0.15
PromoterAI		-0.042	Neutral
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 45

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

Other links and lift over

dbSNP: rs9333378; hg19: chr1-165601466;