14-95535117-G-C

Position:

• chr14-95535117-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016417.3(GLRX5):​c.28G>C​(p.Ala10Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000346 in 1,156,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: GLRX5 NM_016417.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.60

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.322705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLRX5	NM_016417.3	c.28G>C	p.Ala10Pro	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.28G>C	p.Ala10Pro	missense_variant	1/2	1	NM_016417.3	ENSP00000328570.4
GLRX5	ENST00000553672.1	n.301+1314G>C		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000346 AC: 4 AN: 1156880 Hom.: 0 Cov.: 31 AF XY: 0.00000176 AC XY: 1 AN XY: 567606

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000148

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000226

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

May 24, 2024

The c.28G>C (p.A10P) alteration is located in exon 1 (coding exon 1) of the GLRX5 gene. This alteration results from a G to C substitution at nucleotide position 28, causing the alanine (A) at amino acid position 10 to be replaced by a proline (P). 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	0.19
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.074	T
Eigen	Benign	0.072
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.065
Sift	Uncertain	0.014	D
Sift4G	Benign	0.089	T
Polyphen		0.80	P
Vest4		0.41
MutPred		0.46		Gain of glycosylation at A10 (P = 0.0406);
MVP		0.32
MPC		0.73
ClinPred		0.88	D
GERP RS		3.7
Varity_R		0.63
gMVP		0.64

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: rs1371403436; hg19: chr14-96001454;