12-104215816-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001093771.3(TXNRD1):c.14A>G(p.Glu5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000474 in 1,562,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

TXNRD1
NM_001093771.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.03

Publications

3 publications found

Variant links:

Genes affected

TXNRD1 (HGNC:12437): (thioredoxin reductase 1) The protein encoded by this gene belongs to the pyridine nucleotide-disulfide oxidoreductase family, and is a member of the thioredoxin (Trx) system. Three thioredoxin reductase (TrxR) isozymes are found in mammals. TrxRs are selenocysteine-containing flavoenzymes, which reduce thioredoxins, as well as other substrates, and play a key role in redox homoeostasis. This gene encodes an ubiquitously expressed, cytosolic form of TrxR, which functions as a homodimer containing FAD, and selenocysteine (Sec) at the active site. Sec is encoded by UGA codon that normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Alternative splicing, primarily at the 5' end, results in transcript variants encoding same or different isoforms, including a glutaredoxin-containing isoform that is predominantly expressed in testis. [provided by RefSeq, May 2017]

TXNRD1 links:

ENSG00000294348 (HGNC:):

ENSG00000294348 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029791147).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD1	NM_001093771.3 link	c.14A>G	p.Glu5Gly	missense_variant	Exon 1 of 17	ENST00000525566.6	NP_001087240.1	Q16881-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD1	ENST00000525566.6 link	c.14A>G	p.Glu5Gly	missense_variant	Exon 1 of 17	1	NM_001093771.3	ENSP00000434516.1		Q16881-1
ENSG00000294348	ENST00000723050.1 link	n.57-184T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000192

AC:

AN:

161744

AF XY:

0.000114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000225

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1410504

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

696994

show subpopulations

African (AFR)

AF:

0.0000313

AC:

AN:

31996

American (AMR)

AF:

0.00103

AC:

AN:

36846

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25250

East Asian (EAS)

AF:

0.00

AC:

AN:

36714

South Asian (SAS)

AF:

0.00

AC:

AN:

79860

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49462

Middle Eastern (MID)

AF:

0.000876

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00000829

AC:

AN:

1086204

Other (OTH)

AF:

0.0000684

AC:

AN:

58462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000112

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41426

American (AMR)

AF:

0.000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00316

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68022

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.0000620

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 24, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.14A>G (p.E5G) alteration is located in exon 1 (coding exon 1) of the TXNRD1 gene. This alteration results from a A to G substitution at nucleotide position 14, causing the glutamic acid (E) at amino acid position 5 to be replaced by a glycine (G). 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

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.18

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0093

LIST_S2

Benign

0.32

T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.030

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.

PhyloP100

1.0

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.15

N;N

REVEL

Benign

0.080

Sift

Benign

0.042

D;D

Polyphen

0.0080

B;.

Vest4

0.19

MutPred

0.16

Loss of helix (P = 0.028);Loss of helix (P = 0.028);

MVP

0.34

MPC

0.16

ClinPred

0.026

GERP RS

1.0

PromoterAI

0.061

Neutral

(source)

Varity_R

0.039

Mutation Taster

=97/3

polymorphism

(source)

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

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12-104215816-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over