dbSNP rs35264740: TXNDC5:c.1177-366G>A (chr6-7883632-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_030810.5(TXNDC5):c.1177-366G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 152,246 control chromosomes in the GnomAD database, including 17 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 0.014 ( 17 hom., cov: 32)

Consequence

TXNDC5
NM_030810.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.916

Publications

1 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=-0.84).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.014 (2128/152246) while in subpopulation NFE AF = 0.0206 (1400/68020). AF 95% confidence interval is 0.0197. There are 17 homozygotes in GnomAd4. There are 1034 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TXNDC5	NM_030810.5 link	c.1177-366G>A	intron_variant	Intron 9 of 9	ENST00000379757.9	NP_110437.2	Q8NBS9-1
TXNDC5	NM_001145549.4 link	c.853-366G>A	intron_variant	Intron 9 of 9		NP_001139021.1	Q8NBS9-2A0A024QZV0
BLOC1S5-TXNDC5	NR_037616.1 link	n.1336-366G>A	intron_variant	Intron 12 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNDC5	ENST00000379757.9 link	c.1177-366G>A		intron_variant	Intron 9 of 9	1	NM_030810.5	ENSP00000369081.4		Q8NBS9-1
BLOC1S5-TXNDC5	ENST00000439343.2 link	n.*875-366G>A		intron_variant	Intron 12 of 12	2		ENSP00000454697.1		H3BN57

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

2126

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00307

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0146

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00436

Gnomad FIN

AF:

0.0261

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0206

Gnomad OTH

AF:

0.0153

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

GnomAD4 genome

AF:

0.0140

AC:

2128

AN:

152246

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1034

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00306

AC:

127

AN:

41550

American (AMR)

AF:

0.0145

AC:

222

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00477

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0261

AC:

277

AN:

10604

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0206

AC:

1400

AN:

68020

Other (OTH)

AF:

0.0152

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

104

208

312

416

520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0199

Hom.:

Bravo

AF:

0.0121

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

5.4

(source)

DANN

Benign

0.73

PhyloP100

-0.92

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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