3-126607939-C-G

Variant names:

• chr3-126607939-C-G
• rs1231418360
• NM_052883.3:c.1898G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_052883.3(TXNRD3):​c.1898G>C​(p.Gly633Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000737 in 1,356,260 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. G633E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: TXNRD3 NM_052883.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.46
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83

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.1898G>C	p.Gly633Ala	missense	Exon 16 of 16	NP_443115.1	Q86VQ6
	TXNRD3	NM_001173513.3		c.1790G>C	p.Gly597Ala	missense	Exon 15 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.1898G>C	p.Gly633Ala	missense	Exon 16 of 16	ENSP00000430031.4	Q86VQ6
	TXNRD3	ENST00000383572.3	TSL:1	n.92G>C		non_coding_transcript_exon	Exon 2 of 4
	TXNRD3	ENST00000523403.3	TSL:2	c.1790G>C	p.Gly597Ala	missense	Exon 15 of 15	ENSP00000429584.3	H0YBI6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.37e-7 AC: 1 AN: 1356260 Hom.: 0 Cov.: 29 AF XY: 0.00000151 AC XY: 1 AN XY: 663976

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31220

American (AMR) AF: 0.00 AC: 0 AN: 35306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24864

East Asian (EAS) AF: 0.00 AC: 0 AN: 34928

South Asian (SAS) AF: 0.00 AC: 0 AN: 75980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 9.45e-7 AC: 1 AN: 1058336

Other (OTH) AF: 0.00 AC: 0 AN: 56522

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.5
PrimateAI	Uncertain	0.51	T
REVEL	Uncertain	0.55
Sift4G	Uncertain	0.018	D
Vest4		0.47
MVP		0.71
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.39
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs1231418360; hg19: chr3-126326782;