3-126607943-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_052883.3(TXNRD3):c.1894T>C(p.Ser632Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,507,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: TXNRD3 NM_052883.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.46

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TXNRD3	NM_052883.3	c.1894T>C	p.Ser632Pro	missense_variant	16/16	ENST00000524230.9
TXNRD3	NM_001173513.3	c.1786T>C	p.Ser596Pro	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNRD3	ENST00000524230.9	c.1894T>C	p.Ser632Pro	missense_variant	16/16	1	NM_052883.3	P1
TXNRD3	ENST00000383572.3	n.88T>C		non_coding_transcript_exon_variant	2/4	1
TXNRD3	ENST00000523403.3	c.1786T>C	p.Ser596Pro	missense_variant	15/15	2
TXNRD3	ENST00000518740.5	n.271T>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000725 AC: 1 AN: 137988 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 74790

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: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000148 AC: 20 AN: 1355486 Hom.: 0 Cov.: 29 AF XY: 0.0000106 AC XY: 7 AN XY: 663434

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: 0.0000264

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000170

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

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

Nov 30, 2022

The c.1894T>C (p.S632P) alteration is located in exon 16 (coding exon 16) of the TXNRD3 gene. This alteration results from a T to C substitution at nucleotide position 1894, causing the serine (S) at amino acid position 632 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
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
REVEL	Uncertain	0.64
Sift4G	Uncertain	0.0040	D;D;.;.
Vest4		0.69
MVP		0.55
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.69

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: rs966116587; hg19: chr3-126326786;