1-165652002-A-C

Position:

• chr1-165652002-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004528.4(MGST3):​c.216A>C​(p.Leu72Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MGST3 NM_004528.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.412

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MGST3	NM_004528.4	c.216A>C	p.Leu72Phe	missense_variant	4/6	ENST00000367889.8	NP_004519.1
MGST3	XM_047421030.1	c.258A>C	p.Leu86Phe	missense_variant	5/7		XP_047276986.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MGST3	ENST00000367889.8	c.216A>C	p.Leu72Phe	missense_variant	4/6	1	NM_004528.4	ENSP00000356864.3
MGST3	ENST00000367883.3	c.258A>C	p.Leu86Phe	missense_variant	5/7	3		ENSP00000356858.1
MGST3	ENST00000367885.5	c.258A>C	p.Leu86Phe	missense_variant	5/7	2		ENSP00000356860.1
MGST3	ENST00000367884.6	c.216A>C	p.Leu72Phe	missense_variant	5/7	3		ENSP00000356859.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461330 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The c.216A>C (p.L72F) alteration is located in exon 4 (coding exon 3) of the MGST3 gene. This alteration results from a A to C substitution at nucleotide position 216, causing the leucine (L) at amino acid position 72 to be replaced by a phenylalanine (F). 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	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;.;T;.;.
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.94	.;D;.;D;.;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Uncertain	0.0063	D
MutationAssessor	Uncertain	2.4	M;.;.;M;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.0030	D;T;T;D;T;.
Sift4G	Benign	0.13	T;T;T;T;T;T
Polyphen		0.99	D;.;D;D;D;D
Vest4		0.83
MutPred		0.75		.;.;Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.75
MPC		1.2
ClinPred		0.99	D
GERP RS		-6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.86
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-165621239;