rs869312752

chr14-95543952-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_016417.3(GLRX5):c.301A>C(p.Lys101Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLRX5 NM_016417.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.20

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain Glutaredoxin-related protein 5, mitochondrial (size 125) in uniprot entity GLRX5_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_016417.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905
• PP5: Variant 14-95543952-A-C is Pathogenic according to our data. Variant chr14-95543952-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 224510.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLRX5	NM_016417.3	c.301A>C	p.Lys101Gln	missense_variant	2/2	ENST00000331334.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLRX5	ENST00000331334.5	c.301A>C	p.Lys101Gln	missense_variant	2/2	1	NM_016417.3	P1
GLRX5	ENST00000557731.1	c.*679A>C		3_prime_UTR_variant	2/2	5
GLRX5	ENST00000553672.1	n.307A>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Sideroblastic anemia 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
Cadd	Pathogenic	30
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	4.8	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.73		Loss of ubiquitination at K101 (P = 0.0309);
MVP		0.82
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.76

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: rs869312752; hg19: chr14-96010289;