rs1139793

Positions:

chr22-19880695-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006440.5(TXNRD2):c.1109T>C(p.Ile370Thr) variant causes a missense change. The variant allele was found at a frequency of 0.723 in 1,612,762 control chromosomes in the GnomAD database, including 426,057 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 45518 hom., cov: 33)

Exomes 𝑓: 0.72 ( 380539 hom. )

Consequence

TXNRD2
NM_006440.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.83

Variant links:

Genes affected

TXNRD2 (HGNC:18155): (thioredoxin reductase 2) 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 a mitochondrial form important for scavenging reactive oxygen species in mitochondria. It 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. Alternatively spliced transcript variants encoding different isoforms, including a few localized in the cytosol and some lacking the C-terminal Sec residue, have been found for this gene. [provided by RefSeq, Jun 2017]

TXNRD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.917005E-6).

BP6

Variant 22-19880695-A-G is Benign according to our data. Variant chr22-19880695-A-G is described in ClinVar as [Benign]. Clinvar id is 263369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19880695-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.909 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNRD2	NM_006440.5 linkuse as main transcript	c.1109T>C	p.Ile370Thr	missense_variant	13/18	ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7 linkuse as main transcript	c.1109T>C	p.Ile370Thr	missense_variant	13/18	1	NM_006440.5	ENSP00000383365	P4	Q9NNW7-1

Frequencies

GnomAD3 genomes

AF:

0.766

AC:

116456

AN:

152004

Hom.:

45452

Cov.:

show subpopulations

Gnomad AFR

AF:

0.917

Gnomad AMI

AF:

0.892

Gnomad AMR

AF:

0.658

Gnomad ASJ

AF:

0.779

Gnomad EAS

AF:

0.603

Gnomad SAS

AF:

0.581

Gnomad FIN

AF:

0.685

Gnomad MID

AF:

0.797

Gnomad NFE

AF:

0.734

Gnomad OTH

AF:

0.777

GnomAD3 exomes

AF:

0.691

AC:

171567

AN:

248132

Hom.:

60644

AF XY:

0.689

AC XY:

93043

AN XY:

135072

show subpopulations

Gnomad AFR exome

AF:

0.920

Gnomad AMR exome

AF:

0.563

Gnomad ASJ exome

AF:

0.767

Gnomad EAS exome

AF:

0.592

Gnomad SAS exome

AF:

0.579

Gnomad FIN exome

AF:

0.685

Gnomad NFE exome

AF:

0.740

Gnomad OTH exome

AF:

0.706

GnomAD4 exome

AF:

0.719

AC:

1049835

AN:

1460640

Hom.:

380539

Cov.:

AF XY:

0.716

AC XY:

520024

AN XY:

726630

show subpopulations

Gnomad4 AFR exome

AF:

0.926

Gnomad4 AMR exome

AF:

0.578

Gnomad4 ASJ exome

AF:

0.769

Gnomad4 EAS exome

AF:

0.630

Gnomad4 SAS exome

AF:

0.586

Gnomad4 FIN exome

AF:

0.688

Gnomad4 NFE exome

AF:

0.731

Gnomad4 OTH exome

AF:

0.723

GnomAD4 genome

AF:

0.766

AC:

116583

AN:

152122

Hom.:

45518

Cov.:

AF XY:

0.758

AC XY:

56369

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.917

Gnomad4 AMR

AF:

0.658

Gnomad4 ASJ

AF:

0.779

Gnomad4 EAS

AF:

0.602

Gnomad4 SAS

AF:

0.582

Gnomad4 FIN

AF:

0.685

Gnomad4 NFE

AF:

0.734

Gnomad4 OTH

AF:

0.777

Alfa

AF:

0.746

Hom.:

56372

Bravo

AF:

0.773

TwinsUK

AF:

0.726

AC:

2691

ALSPAC

AF:

0.722

AC:

2781

ESP6500AA

AF:

0.916

AC:

3747

ESP6500EA

AF:

0.738

AC:

6182

ExAC

AF:

0.700

AC:

84557

Asia WGS

AF:

0.617

AC:

2148

AN:

3478

EpiCase

AF:

0.749

EpiControl

AF:

0.750

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glucocorticoid deficiency 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 09, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Primary dilated cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.12

.;.;.;.;.;T;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.58

.;T;.;.;.;T;.

MetaRNN

Benign

0.0000029

T;T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.59

.;.;.;.;.;N;.

MutationTaster

Benign

1.0

P;P;P;P;P;P

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.4

N;.;.;N;N;N;.

REVEL

Benign

0.14

Sift

Benign

0.22

T;.;.;T;T;T;.

Sift4G

Benign

0.18

T;T;T;T;T;T;T

Polyphen

0.0

.;.;.;.;.;B;.

Vest4

0.11

MPC

0.26

ClinPred

0.028

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over