3-126611066-C-G

Variant names:

• chr3-126611066-C-G
• rs545536726
• NM_052883.3:c.1699G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_052883.3(TXNRD3):​c.1699G>C​(p.Ala567Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,369,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A567S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TXNRD3 NM_052883.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.38
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052883.3. 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
	TXNRD3	NM_052883.3	MANE Select	c.1699G>C	p.Ala567Pro	missense	Exon 14 of 16	NP_443115.1	Q86VQ6
	TXNRD3	NM_001173513.3		c.1591G>C	p.Ala531Pro	missense	Exon 13 of 15	NP_001166984.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD3	ENST00000524230.9	TSL:1 MANE Select	c.1699G>C	p.Ala567Pro	missense	Exon 14 of 16	ENSP00000430031.4	Q86VQ6
	TXNRD3	ENST00000523403.3	TSL:2	c.1591G>C	p.Ala531Pro	missense	Exon 13 of 15	ENSP00000429584.3	H0YBI6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000759 AC: 1 AN: 131778 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000434

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: 0.00

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1369976 Hom.: 0 Cov.: 27 AF XY: 0.00000148 AC XY: 1 AN XY: 675874

African (AFR) AF: 0.00 AC: 0 AN: 31086

American (AMR) AF: 0.0000288 AC: 1 AN: 34746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24768

East Asian (EAS) AF: 0.00 AC: 0 AN: 35384

South Asian (SAS) AF: 0.00 AC: 0 AN: 76620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 9.34e-7 AC: 1 AN: 1071066

Other (OTH) AF: 0.00 AC: 0 AN: 57272

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		2.4
PrimateAI	Uncertain	0.58	T
REVEL	Pathogenic	0.73
Sift4G	Benign	0.086	T
Vest4		0.77
MVP		0.14
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs545536726; hg19: chr3-126329909;