1-165649842-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_004528.4(MGST3):c.-6C>T variant causes a splice region, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0376 in 1,613,906 control chromosomes in the GnomAD database, including 1,251 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 association (no stars).

• Frequency:
  • Genomes: 𝑓 0.034 (94 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1157 hom.)
• Consequence: MGST3 NM_004528.4 splice_region, 5_prime_UTR
• Scores: Splicing: ADA: 0.00003323
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 0.499

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

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022738874).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0341 (5198/152234) while in subpopulation NFE AF= 0.0408 (2778/68014). AF 95% confidence interval is 0.0396. There are 94 homozygotes in gnomad4. There are 2579 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 94 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MGST3	NM_004528.4	c.-6C>T		splice_region_variant, 5_prime_UTR_variant	2/6	ENST00000367889.8
MGST3	XM_047421030.1	c.37C>T	p.Arg13Cys	missense_variant, splice_region_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MGST3	ENST00000367889.8	c.-6C>T		splice_region_variant, 5_prime_UTR_variant	2/6	1	NM_004528.4	P1

Frequencies

GnomAD3 genomes AF: 0.0342 AC: 5197 AN: 152116 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.0273

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0279

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.0473

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0408

Gnomad OTH AF: 0.0315

GnomAD3 exomes AF: 0.0309 AC: 7779 AN: 251476 Hom.: 146 AF XY: 0.0321 AC XY: 4362 AN XY: 135910

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.0167

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.00625

Gnomad SAS exome AF: 0.0307

Gnomad FIN exome AF: 0.0460

Gnomad NFE exome AF: 0.0390

Gnomad OTH exome AF: 0.0292

GnomAD4 exome AF: 0.0380 AC: 55559 AN: 1461672 Hom.: 1157 Cov.: 31 AF XY: 0.0378 AC XY: 27465 AN XY: 727136

Gnomad4 AFR exome AF: 0.0272

Gnomad4 AMR exome AF: 0.0181

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.00615

Gnomad4 SAS exome AF: 0.0306

Gnomad4 FIN exome AF: 0.0433

Gnomad4 NFE exome AF: 0.0414

Gnomad4 OTH exome AF: 0.0347

GnomAD4 genome AF: 0.0341 AC: 5198 AN: 152234 Hom.: 94 Cov.: 32 AF XY: 0.0346 AC XY: 2579 AN XY: 74440

Gnomad4 AFR AF: 0.0274

Gnomad4 AMR AF: 0.0279

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.0240

Gnomad4 FIN AF: 0.0473

Gnomad4 NFE AF: 0.0408

Gnomad4 OTH AF: 0.0312

Alfa AF: 0.0355 Hom.: 261

Bravo AF: 0.0324

TwinsUK AF: 0.0415 AC: 154

ALSPAC AF: 0.0394 AC: 152

ESP6500AA AF: 0.0281 AC: 124

ESP6500EA AF: 0.0379 AC: 326

ExAC AF: 0.0307 AC: 3723

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.0406

EpiControl AF: 0.0402

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Pulmonary disease, chronic obstructive, susceptibility to Other:1

association, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Jul 05, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	5.9
Dann	Benign	0.94
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.11	N
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PROVEAN	Benign	-0.22	N;N;.
REVEL	Benign	0.047
Sift	Uncertain	0.013	D;D;.
Sift4G	Benign	0.095	T;T;T
Polyphen		0.0090	B;B;B
Vest4		0.061
ClinPred		0.0014	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
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: rs6681; hg19: chr1-165619079;