10-130160872-G-A

Variant summary

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

The NM_006541.5(GLRX3):c.353G>A(p.Ser118Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S118G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRX3 NM_006541.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.43

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]

ACMG classification

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/exons	MANE	UniProt
GLRX3	NM_006541.5	c.353G>A	p.Ser118Asn	missense_variant	4/11	ENST00000331244.10
GLRX3	NM_001199868.2	c.353G>A	p.Ser118Asn	missense_variant	4/12
GLRX3	NM_001321980.2	c.-86G>A		5_prime_UTR_variant	5/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRX3	ENST00000331244.10	c.353G>A	p.Ser118Asn	missense_variant	4/11	1	NM_006541.5	P1
GLRX3	ENST00000481034.1	c.353G>A	p.Ser118Asn	missense_variant, NMD_transcript_variant	4/13	1
GLRX3	ENST00000368644.5	c.353G>A	p.Ser118Asn	missense_variant	4/12	2		P1
GLRX3	ENST00000486974.1	n.241G>A		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

Mar 20, 2023

The c.353G>A (p.S118N) 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 353, causing the serine (S) at amino acid position 118 to be replaced by an asparagine (N). 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	0.091
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.064	T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.65	D
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.69	N;N
REVEL	Benign	0.10
Sift	Benign	0.070	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.0	B;B
Vest4		0.20
MutPred		0.24		Loss of glycosylation at S118 (P = 0.0635);Loss of glycosylation at S118 (P = 0.0635);
MVP		0.15
MPC		0.045
ClinPred		0.18	T
GERP RS		2.4
Varity_R		0.12
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 19

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

Publications

LitVar

Other links and lift over

dbSNP: rs1862562415; hg19: chr10-131959136;