chr1-165649842-C-T

Variant names:

• chr1-165649842-C-T
• rs6681
• NM_004528.4:c.-6C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_004528.4(MGST3):​c.-6C>T variant causes a 5 prime UTR premature start codon gain 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. 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 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.00003323
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 0.499
• Publications: 13 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: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 94 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004528.4. 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
	MGST3	NM_004528.4	MANE Select	c.-6C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	NP_004519.1	O14880
	MGST3	NM_004528.4	MANE Select	c.-6C>T		splice_region	Exon 2 of 6	NP_004519.1	O14880
	MGST3	NM_004528.4	MANE Select	c.-6C>T		5_prime_UTR	Exon 2 of 6	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.-6C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	ENSP00000356864.3	O14880
	MGST3	ENST00000367884.6	TSL:3	c.-6C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 7	ENSP00000356859.1	O14880
	MGST3	ENST00000367889.8	TSL:1 MANE Select	c.-6C>T		splice_region	Exon 2 of 6	ENSP00000356864.3	O14880

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

GnomAD2 exomes AF: 0.0309 AC: 7779 AN: 251476 AF XY: 0.0321

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 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

African (AFR) AF: 0.0272 AC: 910 AN: 33478

American (AMR) AF: 0.0181 AC: 809 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 318 AN: 26134

East Asian (EAS) AF: 0.00615 AC: 244 AN: 39696

South Asian (SAS) AF: 0.0306 AC: 2636 AN: 86254

European-Finnish (FIN) AF: 0.0433 AC: 2312 AN: 53418

Middle Eastern (MID) AF: 0.0316 AC: 179 AN: 5672

European-Non Finnish (NFE) AF: 0.0414 AC: 46059 AN: 1111930

Other (OTH) AF: 0.0347 AC: 2092 AN: 60370

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

African (AFR) AF: 0.0274 AC: 1137 AN: 41552

American (AMR) AF: 0.0279 AC: 426 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3470

East Asian (EAS) AF: 0.00444 AC: 23 AN: 5178

South Asian (SAS) AF: 0.0240 AC: 116 AN: 4826

European-Finnish (FIN) AF: 0.0473 AC: 501 AN: 10582

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0408 AC: 2778 AN: 68014

Other (OTH) AF: 0.0312 AC: 66 AN: 2114

Alfa AF: 0.0358 Hom.: 493

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

ClinVar submissions

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
AlphaMissense	Benign	0.28
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
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.50
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.047
Sift	Uncertain	0.013	D
Sift4G	Benign	0.095	T
Polyphen		0.0090	B
Vest4		0.061
ClinPred		0.0014	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6681; hg19: chr1-165619079;