5-95822464-C-T

Position:

• chr5-95822464-C-T

Variant summary

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

The NM_001118890.2(GLRX):​c.199G>A​(p.Ala67Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,546 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GLRX NM_001118890.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.77

Genes affected

GLRX (HGNC:4330): (glutaredoxin) This gene encodes a member of the glutaredoxin family. The encoded protein is a cytoplasmic enzyme catalyzing the reversible reduction of glutathione-protein mixed disulfides. This enzyme highly contributes to the antioxidant defense system. It is crucial for several signalling pathways by controlling the S-glutathionylation status of signalling mediators. It is involved in beta-amyloid toxicity and Alzheimer's disease. Multiple alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Aug 2011]

RHOBTB3 (HGNC:18757): (Rho related BTB domain containing 3) Enables ATP binding activity and small GTPase binding activity. Involved in retrograde transport, endosome to Golgi. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

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	Protein	UniProt
GLRX	NM_001118890.2	c.199G>A	p.Ala67Thr	missense_variant	1/3	ENST00000237858.11	NP_001112362.1
GLRX	NM_001243658.2	c.199G>A	p.Ala67Thr	missense_variant	1/3		NP_001230587.1
GLRX	NM_001243659.2	c.199G>A	p.Ala67Thr	missense_variant	1/3		NP_001230588.1
GLRX	NM_002064.3	c.199G>A	p.Ala67Thr	missense_variant	1/3		NP_002055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRX	ENST00000237858.11	c.199G>A	p.Ala67Thr	missense_variant	1/3	1	NM_001118890.2	ENSP00000237858	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460546 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726722

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

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

Jun 12, 2023

The c.199G>A (p.A67T) alteration is located in exon 1 (coding exon 1) of the GLRX gene. This alteration results from a G to A substitution at nucleotide position 199, causing the alanine (A) at amino acid position 67 to be replaced by a threonine (T). 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	0.25
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D;D;D;D;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	.;.;.;.;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	3.2	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.016	D;D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.51
MutPred		0.41		Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);
MVP		0.51
MPC		1.0
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.31
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-95158168;