chr3-126611042-C-A

Position:

• chr3-126611042-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_052883.3(TXNRD3):​c.1723G>T​(p.Asp575Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000185 in 1,504,740 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (2 hom.)
• Consequence: TXNRD3 NM_052883.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.01

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15195853).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNRD3	NM_052883.3	c.1723G>T	p.Asp575Tyr	missense_variant	14/16	ENST00000524230.9	NP_443115.1
TXNRD3	NM_001173513.3	c.1615G>T	p.Asp539Tyr	missense_variant	13/15		NP_001166984.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNRD3	ENST00000524230.9	c.1723G>T	p.Asp575Tyr	missense_variant	14/16	1	NM_052883.3	ENSP00000430031.4
TXNRD3	ENST00000523403.3	c.1615G>T	p.Asp539Tyr	missense_variant	13/15	2		ENSP00000429584.3

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152126 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000316 AC: 39 AN: 123322 Hom.: 0 AF XY: 0.000372 AC XY: 25 AN XY: 67162

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: 0.000313

Gnomad FIN exome AF: 0.00359

Gnomad NFE exome AF: 0.000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000164 AC: 222 AN: 1352496 Hom.: 2 Cov.: 26 AF XY: 0.000168 AC XY: 112 AN XY: 666916

Gnomad4 AFR exome AF: 0.0000328

Gnomad4 AMR exome AF: 0.0000307

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000286

Gnomad4 FIN exome AF: 0.00348

Gnomad4 NFE exome AF: 0.0000546

Gnomad4 OTH exome AF: 0.000372

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152244 Hom.: 1 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74438

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00415

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000110 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.000465 AC: 8

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

Feb 17, 2022

The c.1723G>T (p.D575Y) alteration is located in exon 14 (coding exon 14) of the TXNRD3 gene. This alteration results from a G to T substitution at nucleotide position 1723, causing the aspartic acid (D) at amino acid position 575 to be replaced by a tyrosine (Y). 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	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	.;.;.;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;.;.;D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.6	.;.;.;H
PrimateAI	Uncertain	0.51	T
REVEL	Pathogenic	0.73
Sift4G	Uncertain	0.0040	D;D;.;.
Vest4		0.71
MVP		0.38
ClinPred		0.79	D
GERP RS		4.7
Varity_R		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs192442190; hg19: chr3-126329885;