Variant chr3-126608543-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_052883.3(TXNRD3):c.1819C>A(p.Gln607Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,383,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

TXNRD3
NM_052883.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.42

Variant links:

Genes affected

TXNRD3 (HGNC:20667): (thioredoxin reductase 3) 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 the third TrxR, which unlike the other two isozymes, contains an additional N-terminal glutaredoxin (Grx) domain, and shows highest expression in testis. The Grx domain allows this isozyme to participate in both Trx and glutathione systems. It 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. Alternatively spliced transcript variants have been found for this gene. Experimental evidence suggests the use of a non-AUG (CUG) codon as a translation initiation codon (PMID:20018845). [provided by RefSeq, Aug 2017]

TXNRD3 links:

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ACMG classification

Classification made for transcript

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=0.2176067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNRD3	NM_052883.3 link	c.1819C>A	p.Gln607Lys	missense_variant	15/16	ENST00000524230.9	NP_443115.1	Q86VQ6
TXNRD3	NM_001173513.3 link	c.1711C>A	p.Gln571Lys	missense_variant	14/15		NP_001166984.1	Q86VQ6B4DRZ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TXNRD3	ENST00000524230.9 link	c.1819C>A	p.Gln607Lys	missense_variant	15/16	1	NM_052883.3	ENSP00000430031.4	Q86VQ6H0YBQ0
TXNRD3	ENST00000383572.3 link	n.13C>A		non_coding_transcript_exon_variant	1/4	1
TXNRD3	ENST00000523403.3 link	c.1711C>A	p.Gln571Lys	missense_variant	14/15	2		ENSP00000429584.3	H0YBI6
TXNRD3	ENST00000518740.5 link	n.196C>A		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000143

AC:

AN:

139436

Hom.:

AF XY:

0.0000132

AC XY:

AN XY:

75552

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000356

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1383702

Hom.:

Cov.:

AF XY:

0.0000161

AC XY:

AN XY:

682792

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000167

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2024

The c.1819C>A (p.Q607K) alteration is located in exon 15 (coding exon 15) of the TXNRD3 gene. This alteration results from a C to A substitution at nucleotide position 1819, causing the glutamine (Q) at amino acid position 607 to be replaced by a lysine (K). 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

-0.080

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.18

.;.;.;T

Eigen

Benign

-0.23

Eigen_PC

Benign

0.018

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.56

.;.;.;T

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

-0.21

.;.;.;N

PrimateAI

Benign

0.32

REVEL

Uncertain

0.30

Sift4G

Benign

0.91

T;T;.;.

Vest4

0.15

MVP

0.52

ClinPred

0.47

GERP RS

5.2

Varity_R

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over