chr5-134887967-G-A

Position:

chr5-134887967-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_024715.4(TXNDC15):c.376G>A(p.Val126Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000357 in 1,614,206 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00044 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

TXNDC15
NM_024715.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.265

Variant links:

Genes affected

TXNDC15 (HGNC:20652): (thioredoxin domain containing 15) This gene encodes a member of the thioredoxin superfamily. Members of this family are characterized by a conserved active motif called the thioredoxin fold that catalyzes disulfide bond formation and isomerization. [provided by RefSeq, Apr 2017]

TXNDC15 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005326718).

BP6

Variant 5-134887967-G-A is Benign according to our data. Variant chr5-134887967-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1591360.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00044 (67/152320) while in subpopulation EAS AF= 0.00174 (9/5184). AF 95% confidence interval is 0.000972. There are 2 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNDC15	NM_024715.4 linkuse as main transcript	c.376G>A	p.Val126Ile	missense_variant	2/5	ENST00000358387.9	NP_078991.3
TXNDC15	NM_001350735.2 linkuse as main transcript	c.172G>A	p.Val58Ile	missense_variant	2/5		NP_001337664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNDC15	ENST00000358387.9 linkuse as main transcript	c.376G>A	p.Val126Ile	missense_variant	2/5	1	NM_024715.4	ENSP00000351157	P1	Q96J42-1

Frequencies

GnomAD3 genomes

AF:

0.000440

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000521

AC:

131

AN:

251418

Hom.:

AF XY:

0.000581

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00367

Gnomad EAS exome

AF:

0.00125

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000352

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000349

AC:

510

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000360

AC XY:

262

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.00352

Gnomad4 EAS exome

AF:

0.000730

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000263

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000440

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000392

Hom.:

Bravo

AF:

0.000453

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000379

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.376G>A (p.V126I) alteration is located in exon 2 (coding exon 2) of the TXNDC15 gene. This alteration results from a G to A substitution at nucleotide position 376, causing the valine (V) at amino acid position 126 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.70

CADD

Benign

8.5

DANN

Benign

0.76

DEOGEN2

Benign

0.013

T;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.20

T;T;T

M_CAP

Benign

0.0062

MetaRNN

Benign

0.0053

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.13

N;N;N

REVEL

Benign

0.016

Sift

Benign

0.37

T;T;T

Sift4G

Benign

0.60

T;T;T

Polyphen

0.0020

B;.;.

Vest4

0.036

MVP

0.23

MPC

0.15

ClinPred

0.0038

GERP RS

-0.48

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.010

gMVP

0.11

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

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