Genetic Variant TXNDC5:p.Arg403Pro (chr6-7883235-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_030810.5(TXNDC5):c.1208G>C(p.Arg403Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R403Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

TXNDC5
NM_030810.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.98

Publications

13 publications found

Variant links:

Genes affected

TXNDC5 (HGNC:21073): (thioredoxin domain containing 5) This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal endoplasmic reticulum (ER)-signal sequence, three catalytically active thioredoxin domains and a C-terminal ER-retention sequence. Its expression is induced by hypoxia and its role may be to protect hypoxic cells from apoptosis. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the neighboring upstream BLOC1S5 gene. [provided by RefSeq, Dec 2016]

TXNDC5 links:

BLOC1S5-TXNDC5 (HGNC:42001): (BLOC1S5-TXNDC5 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring MUTED (muted homolog) and TXNDC5 (thioredoxin domain containing 5) genes on chromosome 6. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD) and is unlikely to produce a protein product. [provided by RefSeq, Dec 2010]

BLOC1S5-TXNDC5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.825

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030810.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TXNDC5	NM_030810.5	MANE Select	c.1208G>C	p.Arg403Pro	missense	Exon 10 of 10	NP_110437.2
TXNDC5	NM_001145549.4		c.884G>C	p.Arg295Pro	missense	Exon 10 of 10	NP_001139021.1	Q8NBS9-2
BLOC1S5-TXNDC5	NR_037616.1		n.1367G>C		non_coding_transcript_exon	Exon 13 of 13

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TXNDC5	ENST00000379757.9	TSL:1 MANE Select	c.1208G>C	p.Arg403Pro	missense	Exon 10 of 10	ENSP00000369081.4	Q8NBS9-1
TXNDC5	ENST00000473453.2	TSL:1	c.884G>C	p.Arg295Pro	missense	Exon 10 of 10	ENSP00000420784.1	Q8NBS9-2
BLOC1S5-TXNDC5	ENST00000439343.2	TSL:2	n.*906G>C		non_coding_transcript_exon	Exon 13 of 13	ENSP00000454697.1	H3BN57

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.018

MetaRNN

Pathogenic

0.82

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.87

PhyloP100

4.0

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-4.8

REVEL

Benign

0.27

Sift

Uncertain

0.0030

Sift4G

Benign

0.096

Polyphen

1.0

Vest4

0.61

MutPred

0.76

Loss of MoRF binding (P = 0.004)

MVP

0.36

MPC

0.69

ClinPred

0.99

GERP RS

5.8

Varity_R

0.97

gMVP

0.98

Mutation Taster

=31/69

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over