chr14-95543952-A-C

Variant names:

• chr14-95543952-A-C
• rs869312752
• NM_016417.3:c.301A>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K101N) has been classified as Uncertain significance.

• 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
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• sideroblastic anemia 3

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• spasticity-ataxia-gait anomalies syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• 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 VariationId is 224510.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016417.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRX5	NM_016417.3	MANE Select	c.301A>C	p.Lys101Gln	missense	Exon 2 of 2	NP_057501.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRX5	ENST00000331334.5	TSL:1 MANE Select	c.301A>C	p.Lys101Gln	missense	Exon 2 of 2	ENSP00000328570.4	Q86SX6
	GLRX5	ENST00000557731.1	TSL:5	c.*679A>C		3_prime_UTR	Exon 2 of 2	ENSP00000451800.1	H0YJM6
	GLRX5	ENST00000902982.1		c.296-4A>C		splice_region intron	N/A	ENSP00000573041.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Sideroblastic anemia 3 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.2
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
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs869312752; hg19: chr14-96010289;