Genetic Variant GLRX3:p.Arg99Gln (chr10-130160815-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006541.5(GLRX3):c.296G>A(p.Arg99Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000482 in 1,596,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

GLRX3
NM_006541.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.36

Variant links:

Genes affected

GLRX3 (HGNC:15987): (glutaredoxin 3) This gene encodes a member of the glutaredoxin family. Glutaredoxins are oxidoreductase enzymes that reduce a variety of substrates using glutathione as a cofactor. The encoded protein binds to and modulates the function of protein kinase C theta. The encoded protein may also inhibit apoptosis and play a role in cellular growth, and the expression of this gene may be a marker for cancer. Pseudogenes of this gene are located on the short arm of chromosomes 6 and 9. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Dec 2010]

GLRX3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1182169).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRX3	NM_006541.5 link	c.296G>A	p.Arg99Gln	missense_variant	Exon 4 of 11	ENST00000331244.10	NP_006532.2	O76003A0A140VJK1
GLRX3	NM_001199868.2 link	c.296G>A	p.Arg99Gln	missense_variant	Exon 4 of 12		NP_001186797.1	O76003A0A140VJK1
GLRX3	NM_001321980.2 link	c.-143G>A		5_prime_UTR_variant	Exon 5 of 12		NP_001308909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GLRX3	ENST00000331244.10 link	c.296G>A	p.Arg99Gln	missense_variant	Exon 4 of 11	1	NM_006541.5	ENSP00000330836.5	O76003
GLRX3	ENST00000481034.1 link	n.296G>A		non_coding_transcript_exon_variant	Exon 4 of 13	1		ENSP00000435445.1	O76003
GLRX3	ENST00000368644.5 link	c.296G>A	p.Arg99Gln	missense_variant	Exon 4 of 12	2		ENSP00000357633.1	O76003
GLRX3	ENST00000486974.1 link	n.184G>A		non_coding_transcript_exon_variant	Exon 3 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251386

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.0000485

AC:

AN:

1444572

Hom.:

Cov.:

AF XY:

0.0000542

AC XY:

AN XY:

719888

show subpopulations

Gnomad4 AFR exome

AF:

0.0000603

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000654

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000283

Gnomad4 OTH exome

AF:

0.000234

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.296G>A (p.R99Q) alteration is located in exon 4 (coding exon 4) of the GLRX3 gene. This alteration results from a G to A substitution at nucleotide position 296, causing the arginine (R) at amino acid position 99 to be replaced by a glutamine (Q). 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

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-0.032

Eigen_PC

Benign

0.036

FATHMM_MKL

Uncertain

0.92

M_CAP

Benign

0.0030

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.4

N;N

REVEL

Benign

0.089

Sift

Benign

0.050

D;D

Sift4G

Benign

0.12

T;T

Polyphen

0.44

B;B

Vest4

0.22

MVP

0.35

MPC

0.054

ClinPred

0.079

GERP RS

2.6

Varity_R

0.25

gMVP

0.69

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