5-95822475-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001118890.2(GLRX):c.188A>T(p.Gln63Leu) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRX NM_001118890.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24572554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRX	NM_001118890.2	c.188A>T	p.Gln63Leu	missense_variant	1/3	ENST00000237858.11
GLRX	NM_001243658.2	c.188A>T	p.Gln63Leu	missense_variant	1/3
GLRX	NM_001243659.2	c.188A>T	p.Gln63Leu	missense_variant	1/3
GLRX	NM_002064.3	c.188A>T	p.Gln63Leu	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRX	ENST00000237858.11	c.188A>T	p.Gln63Leu	missense_variant	1/3	1	NM_001118890.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jan 27, 2022

The c.188A>T (p.Q63L) alteration is located in exon 1 (coding exon 1) of the GLRX gene. This alteration results from a A to T substitution at nucleotide position 188, causing the glutamine (Q) at amino acid position 63 to be replaced by a leucine (L). 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	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.77	D;D;D;D;D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.66	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-5.1	D;D;D;D;D
REVEL	Benign	0.083
Sift	Uncertain	0.0070	D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D
Polyphen		0.11	B;B;B;B;B
Vest4		0.33
MutPred		0.42		Loss of disorder (P = 0.109);Loss of disorder (P = 0.109);Loss of disorder (P = 0.109);Loss of disorder (P = 0.109);Loss of disorder (P = 0.109);
MVP		0.47
MPC		0.42
ClinPred		0.98	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.50

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: chr5-95158179;