chr12-104333966-G-C

Variant names:

• chr12-104333966-G-C
• rs4630362
• NM_001093771.3:c.1651-271G>C

Variant summary

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

The ENST00000525566.6(TXNRD1):​c.1651-271G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.926 in 152,260 control chromosomes in the GnomAD database, including 65,482 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 0.93 (65482 hom., cov: 32)
• Consequence: TXNRD1 ENST00000525566.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.745
• Publications: 5 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000525566.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD1	NM_001093771.3	MANE Select	c.1651-271G>C		intron	N/A	NP_001087240.1
	TXNRD1	NM_003330.4		c.1357-271G>C		intron	N/A	NP_003321.3
	TXNRD1	NM_001261445.2		c.1351-271G>C		intron	N/A	NP_001248374.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD1	ENST00000525566.6	TSL:1 MANE Select	c.1651-271G>C		intron	N/A	ENSP00000434516.1
	TXNRD1	ENST00000526691.5	TSL:1	c.1357-271G>C		intron	N/A	ENSP00000435929.1
	TXNRD1	ENST00000503506.6	TSL:1	c.1201-271G>C		intron	N/A	ENSP00000421934.2

Frequencies

GnomAD3 genomes AF: 0.926 AC: 140931 AN: 152142 Hom.: 65428 Cov.: 32

Gnomad AFR AF: 0.981

Gnomad AMI AF: 0.899

Gnomad AMR AF: 0.894

Gnomad ASJ AF: 0.937

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.940

Gnomad FIN AF: 0.896

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.898

Gnomad OTH AF: 0.931

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.926 AC: 141044 AN: 152260 Hom.: 65482 Cov.: 32 AF XY: 0.926 AC XY: 68958 AN XY: 74446

African (AFR) AF: 0.981 AC: 40763 AN: 41560

American (AMR) AF: 0.894 AC: 13653 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.937 AC: 3252 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5181 AN: 5186

South Asian (SAS) AF: 0.940 AC: 4534 AN: 4824

European-Finnish (FIN) AF: 0.896 AC: 9491 AN: 10594

Middle Eastern (MID) AF: 0.973 AC: 286 AN: 294

European-Non Finnish (NFE) AF: 0.898 AC: 61095 AN: 68024

Other (OTH) AF: 0.931 AC: 1969 AN: 2114

Alfa AF: 0.913 Hom.: 7877

Bravo AF: 0.927

Asia WGS AF: 0.973 AC: 3384 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.64
DANN	Benign	0.60
PhyloP100		-0.74
Mutation Taster		=100/0	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: rs4630362; hg19: chr12-104727744;