rs4595619

Positions:

• chr12-104321931-A-G
• chr12-104321931-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001093771.3(TXNRD1):​c.1215+615A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 151,908 control chromosomes in the GnomAD database, including 17,643 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 0.47 (17643 hom., cov: 31)
• Consequence: TXNRD1 NM_001093771.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.163

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TXNRD1	NM_001093771.3	c.1215+615A>G		intron_variant		ENST00000525566.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNRD1	ENST00000525566.6	c.1215+615A>G		intron_variant		1	NM_001093771.3	P1

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71640 AN: 151794 Hom.: 17643 Cov.: 31

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.540

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.621

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.510

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

GnomAD4 genome AF: 0.472 AC: 71655 AN: 151908 Hom.: 17643 Cov.: 31 AF XY: 0.466 AC XY: 34578 AN XY: 74240

Gnomad4 AFR AF: 0.326

Gnomad4 AMR AF: 0.499

Gnomad4 ASJ AF: 0.522

Gnomad4 EAS AF: 0.620

Gnomad4 SAS AF: 0.506

Gnomad4 FIN AF: 0.412

Gnomad4 NFE AF: 0.545

Gnomad4 OTH AF: 0.513

Alfa AF: 0.496 Hom.: 2320

Bravo AF: 0.475

Asia WGS AF: 0.534 AC: 1856 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.0
DANN	Benign	0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs4595619; hg19: chr12-104715709;