Genetic Variant TXNDC5:c.964-629T>C (chr6-7886672-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_030810.5(TXNDC5):c.964-629T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,222 control chromosomes in the GnomAD database, including 2,821 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 0.17 ( 2821 hom., cov: 33)

Consequence

TXNDC5
NM_030810.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.790

Publications

14 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TXNDC5	NM_030810.5 link	c.964-629T>C	intron_variant	Intron 7 of 9	ENST00000379757.9	NP_110437.2	Q8NBS9-1
TXNDC5	NM_001145549.4 link	c.640-629T>C	intron_variant	Intron 7 of 9		NP_001139021.1	Q8NBS9-2A0A024QZV0
BLOC1S5-TXNDC5	NR_037616.1 link	n.1123-629T>C	intron_variant	Intron 10 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNDC5	ENST00000379757.9 link	c.964-629T>C		intron_variant	Intron 7 of 9	1	NM_030810.5	ENSP00000369081.4		Q8NBS9-1
BLOC1S5-TXNDC5	ENST00000439343.2 link	n.*662-629T>C		intron_variant	Intron 10 of 12	2		ENSP00000454697.1		H3BN57

Frequencies

GnomAD3 genomes

AF:

0.172

AC:

26184

AN:

152104

Hom.:

2812

Cov.:

show subpopulations

Gnomad AFR

AF:

0.311

Gnomad AMI

AF:

0.0725

Gnomad AMR

AF:

0.126

Gnomad ASJ

AF:

0.0957

Gnomad EAS

AF:

0.120

Gnomad SAS

AF:

0.113

Gnomad FIN

AF:

0.173

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.142

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.172

AC:

26225

AN:

152222

Hom.:

2821

Cov.:

AF XY:

0.174

AC XY:

12974

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.311

AC:

12905

AN:

41518

American (AMR)

AF:

0.126

AC:

1932

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0957

AC:

332

AN:

3470

East Asian (EAS)

AF:

0.120

AC:

620

AN:

5176

South Asian (SAS)

AF:

0.113

AC:

546

AN:

4816

European-Finnish (FIN)

AF:

0.173

AC:

1831

AN:

10598

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.112

AC:

7641

AN:

68028

Other (OTH)

AF:

0.144

AC:

304

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1060

2120

3179

4239

5299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

270

540

810

1080

1350

<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:

0.125

Hom.:

1142

Bravo

AF:

0.176

Asia WGS

AF:

0.152

AC:

528

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.0050

(source)

DANN

Benign

0.71

PhyloP100

-0.79

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over