12-104310058-A-G

Variant names:

• chr12-104310058-A-G
• rs7134193
• NM_001093771.3:c.415-1232A>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.415-1232A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,534,796 control chromosomes in the GnomAD database, including 41,970 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 0.23 (4111 hom., cov: 32)
  • Exomes 𝑓: 0.23 (37859 hom.)
• Consequence: TXNRD1 NM_001093771.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.76
• Publications: 6 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 (MetaRNN=0.0047516227).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD1	NM_001093771.3	c.415-1232A>G		intron_variant	Intron 4 of 16	ENST00000525566.6	NP_001087240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD1	ENST00000525566.6	c.415-1232A>G		intron_variant	Intron 4 of 16	1	NM_001093771.3	ENSP00000434516.1

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34812 AN: 151874 Hom.: 4105 Cov.: 32

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.0204

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.226

GnomAD2 exomes AF: 0.203 AC: 27268 AN: 134078 AF XY: 0.212

Gnomad AFR exome AF: 0.266

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.0197

Gnomad FIN exome AF: 0.215

Gnomad NFE exome AF: 0.235

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.229 AC: 317222 AN: 1382802 Hom.: 37859 Cov.: 33 AF XY: 0.231 AC XY: 157234 AN XY: 682116

African (AFR) AF: 0.275 AC: 8679 AN: 31586

American (AMR) AF: 0.138 AC: 4908 AN: 35686

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 6421 AN: 25132

East Asian (EAS) AF: 0.0149 AC: 532 AN: 35686

South Asian (SAS) AF: 0.256 AC: 20319 AN: 79220

European-Finnish (FIN) AF: 0.200 AC: 6773 AN: 33946

Middle Eastern (MID) AF: 0.289 AC: 1645 AN: 5690

European-Non Finnish (NFE) AF: 0.236 AC: 254752 AN: 1077982

Other (OTH) AF: 0.228 AC: 13193 AN: 57874

GnomAD4 genome AF: 0.229 AC: 34847 AN: 151994 Hom.: 4111 Cov.: 32 AF XY: 0.228 AC XY: 16957 AN XY: 74272

African (AFR) AF: 0.265 AC: 10966 AN: 41430

American (AMR) AF: 0.179 AC: 2738 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 943 AN: 3468

East Asian (EAS) AF: 0.0202 AC: 105 AN: 5188

South Asian (SAS) AF: 0.246 AC: 1183 AN: 4814

European-Finnish (FIN) AF: 0.214 AC: 2256 AN: 10538

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15837 AN: 67976

Other (OTH) AF: 0.226 AC: 476 AN: 2108

Alfa AF: 0.229 Hom.: 1217

Bravo AF: 0.223

TwinsUK AF: 0.229 AC: 848

ALSPAC AF: 0.232 AC: 895

ExAC AF: 0.206 AC: 3491

Asia WGS AF: 0.168 AC: 586 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.064
DANN	Benign	0.52
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.34	T;.
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-1.1	T
PhyloP100		-1.8
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.14
Sift	Benign	0.14	T;T
Sift4G	Benign	1.0	T;T
Vest4		0.025
ClinPred		0.014	T
GERP RS		-11
PromoterAI		-0.0026	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs7134193; hg19: chr12-104703836; COSMIC: COSV61597298; COSMIC: COSV61597298;