dbSNP rs9502656: TXNDC5:p.Asp430Asp (chr6-7883153-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_030810.5(TXNDC5):c.1290C>T(p.Asp430Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0279 in 1,614,084 control chromosomes in the GnomAD database, including 2,118 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 0.074 ( 1003 hom., cov: 32)

Exomes 𝑓: 0.023 ( 1115 hom. )

Consequence

TXNDC5
NM_030810.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.768

Publications

5 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP7

Synonymous conserved (PhyloP=-0.768 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNDC5	NM_030810.5 link	c.1290C>T	p.Asp430Asp	synonymous_variant	Exon 10 of 10	ENST00000379757.9	NP_110437.2	Q8NBS9-1
TXNDC5	NM_001145549.4 link	c.966C>T	p.Asp322Asp	synonymous_variant	Exon 10 of 10		NP_001139021.1	Q8NBS9-2A0A024QZV0
BLOC1S5-TXNDC5	NR_037616.1 link	n.1449C>T		non_coding_transcript_exon_variant	Exon 13 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TXNDC5	ENST00000379757.9 link	c.1290C>T	p.Asp430Asp	synonymous_variant	Exon 10 of 10	1	NM_030810.5	ENSP00000369081.4	Q8NBS9-1
BLOC1S5-TXNDC5	ENST00000439343.2 link	n.*988C>T		non_coding_transcript_exon_variant	Exon 13 of 13	2		ENSP00000454697.1	H3BN57
BLOC1S5-TXNDC5	ENST00000439343.2 link	n.*988C>T		3_prime_UTR_variant	Exon 13 of 13	2		ENSP00000454697.1	H3BN57

Frequencies

GnomAD3 genomes

AF:

0.0736

AC:

11193

AN:

152106

Hom.:

1003

Cov.:

show subpopulations

Gnomad AFR

AF:

0.214

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0467

Gnomad ASJ

AF:

0.0280

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.00593

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0188

Gnomad OTH

AF:

0.0618

GnomAD2 exomes

AF:

0.0295

AC:

7429

AN:

251442

AF XY:

0.0252

show subpopulations

Gnomad AFR exome

AF:

0.217

Gnomad AMR exome

AF:

0.0258

Gnomad ASJ exome

AF:

0.0266

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00688

Gnomad NFE exome

AF:

0.0196

Gnomad OTH exome

AF:

0.0256

GnomAD4 exome

AF:

0.0232

AC:

33843

AN:

1461860

Hom.:

1115

Cov.:

AF XY:

0.0222

AC XY:

16137

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.220

AC:

7361

AN:

33476

American (AMR)

AF:

0.0269

AC:

1203

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0250

AC:

654

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00777

AC:

670

AN:

86258

European-Finnish (FIN)

AF:

0.00753

AC:

402

AN:

53408

Middle Eastern (MID)

AF:

0.0406

AC:

234

AN:

5766

European-Non Finnish (NFE)

AF:

0.0193

AC:

21517

AN:

1112002

Other (OTH)

AF:

0.0298

AC:

1801

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1812

3624

5437

7249

9061

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

954

1908

2862

3816

4770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0736

AC:

11208

AN:

152224

Hom.:

1003

Cov.:

AF XY:

0.0723

AC XY:

5381

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.214

AC:

8883

AN:

41504

American (AMR)

AF:

0.0466

AC:

713

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0280

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00539

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00593

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0187

AC:

1275

AN:

68014

Other (OTH)

AF:

0.0602

AC:

127

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

470

939

1409

1878

2348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0471

Hom.:

287

Bravo

AF:

0.0828

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0218

EpiControl

AF:

0.0220

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.29

(source)

DANN

Benign

0.82

PhyloP100

-0.77

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over