rs35009941

Variant names:

• chr12-104288750-C-G
• rs35009941
• NM_001093771.3:c.305-181C>G

Variant summary

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

The NM_001093771.3(TXNRD1):​c.305-181C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,478,786 control chromosomes in the GnomAD database, including 875 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 0.038 (297 hom., cov: 32)
  • Exomes 𝑓: 0.011 (578 hom.)
• Consequence: TXNRD1 NM_001093771.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.299
• Publications: 10 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001093771.3. 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
	TXNRD1	NM_001093771.3	MANE Select	c.305-181C>G		intron	N/A	NP_001087240.1	Q16881-1
	TXNRD1	NM_003330.4		c.11-181C>G		intron	N/A	NP_003321.3
	TXNRD1	NM_001261445.2		c.5-181C>G		intron	N/A	NP_001248374.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD1	ENST00000525566.6	TSL:1 MANE Select	c.305-181C>G		intron	N/A	ENSP00000434516.1	Q16881-1
	TXNRD1	ENST00000526691.5	TSL:1	c.11-181C>G		intron	N/A	ENSP00000435929.1	Q16881-4
	TXNRD1	ENST00000503506.6	TSL:1	c.-146-181C>G		intron	N/A	ENSP00000421934.2	Q16881-5

Frequencies

GnomAD3 genomes AF: 0.0384 AC: 5841 AN: 152154 Hom.: 293 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.0196

Gnomad SAS AF: 0.0770

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.0315

GnomAD2 exomes AF: 0.0267 AC: 3284 AN: 122798 AF XY: 0.0282

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.0245

Gnomad EAS exome AF: 0.0206

Gnomad FIN exome AF: 0.000383

Gnomad NFE exome AF: 0.00356

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0108 AC: 14273 AN: 1326514 Hom.: 578 Cov.: 30 AF XY: 0.0124 AC XY: 8041 AN XY: 648990

African (AFR) AF: 0.117 AC: 3528 AN: 30048

American (AMR) AF: 0.0150 AC: 441 AN: 29480

Ashkenazi Jewish (ASJ) AF: 0.0232 AC: 506 AN: 21818

East Asian (EAS) AF: 0.0215 AC: 722 AN: 33526

South Asian (SAS) AF: 0.0762 AC: 5696 AN: 74778

European-Finnish (FIN) AF: 0.000199 AC: 7 AN: 35158

Middle Eastern (MID) AF: 0.0407 AC: 217 AN: 5332

European-Non Finnish (NFE) AF: 0.00197 AC: 2049 AN: 1041506

Other (OTH) AF: 0.0202 AC: 1107 AN: 54868

GnomAD4 genome AF: 0.0385 AC: 5857 AN: 152272 Hom.: 297 Cov.: 32 AF XY: 0.0384 AC XY: 2858 AN XY: 74460

African (AFR) AF: 0.111 AC: 4611 AN: 41530

American (AMR) AF: 0.0269 AC: 412 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3472

East Asian (EAS) AF: 0.0193 AC: 100 AN: 5182

South Asian (SAS) AF: 0.0760 AC: 367 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10614

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00304 AC: 207 AN: 68022

Other (OTH) AF: 0.0312 AC: 66 AN: 2114

Alfa AF: 0.0210 Hom.: 23

Bravo AF: 0.0426

Asia WGS AF: 0.0490 AC: 170 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.7
DANN	Benign	0.52
PhyloP100		-0.30
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=294/6	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: rs35009941; hg19: chr12-104682528;