12-104251602-G-C

Position:

• chr12-104251602-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000525566.6(TXNRD1):​c.167G>C​(p.Arg56Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,613,938 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00071 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (11 hom.)
• Consequence: TXNRD1 ENST00000525566.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.490

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051448345).
• BP6: Variant 12-104251602-G-C is Benign according to our data. Variant chr12-104251602-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 725773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNRD1	NM_001093771.3	c.167G>C	p.Arg56Thr	missense_variant	2/17	ENST00000525566.6	NP_001087240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNRD1	ENST00000525566.6	c.167G>C	p.Arg56Thr	missense_variant	2/17	1	NM_001093771.3	ENSP00000434516	P1
TXNRD1	ENST00000526006.1	n.57G>C		non_coding_transcript_exon_variant	1/5	1
TXNRD1	ENST00000534282.1	n.162G>C		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152136 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00148 AC: 368 AN: 249308 Hom.: 5 AF XY: 0.00175 AC XY: 237 AN XY: 135254

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00703

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00104 AC: 1523 AN: 1461684 Hom.: 11 Cov.: 47 AF XY: 0.00122 AC XY: 886 AN XY: 727128

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00620

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000741

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000709 AC: 108 AN: 152254 Hom.: 1 Cov.: 33 AF XY: 0.000766 AC XY: 57 AN XY: 74440

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000912

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000680

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00106 AC: 9

ExAC AF: 0.00154 AC: 187

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00213

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 21, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.8
DANN	Benign	0.72
DEOGEN2	Benign	0.30	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.42	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0051	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.69	N;N
REVEL	Benign	0.060
Sift	Benign	0.15	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.73	P;.
Vest4		0.20
MVP		0.60
MPC		0.20
ClinPred		0.0052	T
GERP RS		0.88
Varity_R		0.045

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: rs200693410; hg19: chr12-104645380;