14-95535114-G-A

Position:

• chr14-95535114-G-A

Variant summary

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

The NM_016417.3(GLRX5):​c.25G>A​(p.Ala9Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000605 in 1,156,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000061 (0 hom.)
• Consequence: GLRX5 NM_016417.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.59

Genes affected

GLRX5 (HGNC:20134): (glutaredoxin 5) This gene encodes a mitochondrial protein, which is evolutionarily conserved. It is involved in the biogenesis of iron-sulfur clusters, which are required for normal iron homeostasis. Mutations in this gene are associated with autosomal recessive pyridoxine-refractory sideroblastic anemia. [provided by RefSeq, May 2010]

GLRX5 (HGNC:):

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=0.1171543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRX5	NM_016417.3	c.25G>A	p.Ala9Thr	missense_variant	1/2	ENST00000331334.5	NP_057501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLRX5	ENST00000331334.5	c.25G>A	p.Ala9Thr	missense_variant	1/2	1	NM_016417.3	ENSP00000328570.4
GLRX5	ENST00000553672.1	n.301+1311G>A		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000605 AC: 7 AN: 1156522 Hom.: 0 Cov.: 31 AF XY: 0.00000352 AC XY: 2 AN XY: 567682

Gnomad4 AFR exome AF: 0.000217

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: 0.00

Gnomad4 OTH exome AF: 0.0000452

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2021

The c.25G>A (p.A9T) alteration is located in exon 1 (coding exon 1) of the GLRX5 gene. This alteration results from a G to A substitution at nucleotide position 25, causing the alanine (A) at amino acid position 9 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 21, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with GLRX5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 9 of the GLRX5 protein (p.Ala9Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.069
Sift	Benign	0.65	T
Sift4G	Benign	0.87	T
Polyphen		0.041	B
Vest4		0.19
MutPred		0.41		Gain of catalytic residue at A9 (P = 0.0228);
MVP		0.47
MPC		0.55
ClinPred		0.38	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.075
gMVP		0.74

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

Other links and lift over

dbSNP: rs1168665176; hg19: chr14-96001451;