Genetic Variant NM_004528.4:c.83A>G (chr1-165649930-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004528.4(MGST3):c.83A>G(p.Asn28Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

MGST3
NM_004528.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.59

Variant links:

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]

MGST3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MGST3	NM_004528.4 link	c.83A>G	p.Asn28Ser	missense_variant	Exon 2 of 6	ENST00000367889.8	NP_004519.1	O14880A0A024R8Z1
MGST3	XM_047421030.1 link	c.125A>G	p.Asn42Ser	missense_variant	Exon 3 of 7		XP_047276986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MGST3	ENST00000367889.8 link	c.83A>G	p.Asn28Ser	missense_variant	Exon 2 of 6	1	NM_004528.4	ENSP00000356864.3	O14880
MGST3	ENST00000367883.3 link	c.125A>G	p.Asn42Ser	missense_variant	Exon 3 of 7	3		ENSP00000356858.1	Q5VV89
MGST3	ENST00000367885.5 link	c.125A>G	p.Asn42Ser	missense_variant	Exon 3 of 7	2		ENSP00000356860.1	Q5VV89
MGST3	ENST00000367884.6 link	c.83A>G	p.Asn28Ser	missense_variant	Exon 3 of 7	3		ENSP00000356859.1	O14880

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251486

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.83A>G (p.N28S) alteration is located in exon 2 (coding exon 1) of the MGST3 gene. This alteration results from a A to G substitution at nucleotide position 83, causing the asparagine (N) at amino acid position 28 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;.;.;T;.;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

.;D;.;D;.;D

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.53

D;D;D;D;D;D

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.7

M;.;.;M;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.3

N;N;N;N;N;.

REVEL

Benign

0.19

Sift

Benign

0.066

T;T;T;T;T;.

Sift4G

Benign

0.11

T;T;T;T;T;T

Polyphen

0.63

P;.;P;P;P;P

Vest4

0.49

MutPred

0.58

.;.;Gain of disorder (P = 0.0452);.;Gain of disorder (P = 0.0452);Gain of disorder (P = 0.0452);

MVP

0.66

MPC

0.50

ClinPred

0.18

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over