12-104286883-G-T

Variant names:

• chr12-104286883-G-T
• rs10735393
• ENST00000526691.5:c.-454G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000526691.5(TXNRD1):​c.-454G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.873 in 1,105,226 control chromosomes in the GnomAD database, including 422,586 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.83 (53335 hom., cov: 33)
  • Exomes 𝑓: 0.88 (369251 hom.)
• Consequence: TXNRD1 ENST00000526691.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• Publications: 9 publications found

Genes affected

TXNRD1 (HGNC:12437): (thioredoxin reductase 1) 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 an ubiquitously expressed, cytosolic form of TrxR, which 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. Alternative splicing, primarily at the 5' end, results in transcript variants encoding same or different isoforms, including a glutaredoxin-containing isoform that is predominantly expressed in testis. [provided by RefSeq, May 2017]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.881 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000526691.5. 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
	TXNRD1	NM_001093771.3	MANE Select	c.305-2048G>T		intron	N/A	NP_001087240.1	Q16881-1
	TXNRD1	NM_003330.4		c.-454G>T		upstream_gene	N/A	NP_003321.3
	TXNRD1	NM_001261445.2		c.-545G>T		upstream_gene	N/A	NP_001248374.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD1	ENST00000526691.5	TSL:1	c.-454G>T		5_prime_UTR	Exon 1 of 15	ENSP00000435929.1	Q16881-4
	TXNRD1	ENST00000503506.6	TSL:1	c.-373G>T		5_prime_UTR	Exon 1 of 15	ENSP00000421934.2	Q16881-5
	TXNRD1	ENST00000525566.6	TSL:1 MANE Select	c.305-2048G>T		intron	N/A	ENSP00000434516.1	Q16881-1

Frequencies

GnomAD3 genomes AF: 0.835 AC: 126962 AN: 152094 Hom.: 53311 Cov.: 33

Gnomad AFR AF: 0.753

Gnomad AMI AF: 0.899

Gnomad AMR AF: 0.788

Gnomad ASJ AF: 0.906

Gnomad EAS AF: 0.841

Gnomad SAS AF: 0.837

Gnomad FIN AF: 0.844

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.887

Gnomad OTH AF: 0.854

GnomAD4 exome AF: 0.880 AC: 838364 AN: 953014 Hom.: 369251 Cov.: 57 AF XY: 0.879 AC XY: 394972 AN XY: 449344

African (AFR) AF: 0.754 AC: 14747 AN: 19548

American (AMR) AF: 0.763 AC: 4264 AN: 5588

Ashkenazi Jewish (ASJ) AF: 0.910 AC: 7212 AN: 7926

East Asian (EAS) AF: 0.837 AC: 7822 AN: 9342

South Asian (SAS) AF: 0.836 AC: 31552 AN: 37724

European-Finnish (FIN) AF: 0.849 AC: 5243 AN: 6176

Middle Eastern (MID) AF: 0.912 AC: 1896 AN: 2078

European-Non Finnish (NFE) AF: 0.886 AC: 736732 AN: 831298

Other (OTH) AF: 0.867 AC: 28896 AN: 33334

GnomAD4 genome AF: 0.835 AC: 127033 AN: 152212 Hom.: 53335 Cov.: 33 AF XY: 0.831 AC XY: 61883 AN XY: 74432

African (AFR) AF: 0.753 AC: 31266 AN: 41518

American (AMR) AF: 0.787 AC: 12028 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.906 AC: 3145 AN: 3472

East Asian (EAS) AF: 0.840 AC: 4359 AN: 5188

South Asian (SAS) AF: 0.838 AC: 4046 AN: 4826

European-Finnish (FIN) AF: 0.844 AC: 8938 AN: 10588

Middle Eastern (MID) AF: 0.946 AC: 278 AN: 294

European-Non Finnish (NFE) AF: 0.887 AC: 60347 AN: 68018

Other (OTH) AF: 0.854 AC: 1806 AN: 2114

Alfa AF: 0.860 Hom.: 33334

Bravo AF: 0.825

Asia WGS AF: 0.815 AC: 2833 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.84
DANN	Benign	0.71
PhyloP100		-1.3
PromoterAI		-0.043	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs10735393; hg19: chr12-104680661;