rs1225936

Variant names:

• chr6-7884951-C-A
• rs1225936
• NM_030810.5:c.1047-463G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_030810.5(TXNDC5):​c.1047-463G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0375 in 152,276 control chromosomes in the GnomAD database, including 134 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 0.038 (134 hom., cov: 32)
• Consequence: TXNDC5 NM_030810.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.164
• Publications: 5 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0375 (5714/152276) while in subpopulation NFE AF = 0.0497 (3380/68012). AF 95% confidence interval is 0.0483. There are 134 homozygotes in GnomAd4. There are 2636 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 134 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNDC5	NM_030810.5	c.1047-463G>T		intron_variant	Intron 8 of 9	ENST00000379757.9	NP_110437.2
TXNDC5	NM_001145549.4	c.723-463G>T		intron_variant	Intron 8 of 9		NP_001139021.1
BLOC1S5-TXNDC5	NR_037616.1	n.1206-463G>T		intron_variant	Intron 11 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNDC5	ENST00000379757.9	c.1047-463G>T		intron_variant	Intron 8 of 9	1	NM_030810.5	ENSP00000369081.4
BLOC1S5-TXNDC5	ENST00000439343.2	n.*745-463G>T		intron_variant	Intron 11 of 12	2		ENSP00000454697.1

Frequencies

GnomAD3 genomes AF: 0.0376 AC: 5720 AN: 152158 Hom.: 134 Cov.: 32

Gnomad AFR AF: 0.0258

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0362

Gnomad ASJ AF: 0.0766

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0311

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0497

Gnomad OTH AF: 0.0511

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

GnomAD4 genome AF: 0.0375 AC: 5714 AN: 152276 Hom.: 134 Cov.: 32 AF XY: 0.0354 AC XY: 2636 AN XY: 74442

African (AFR) AF: 0.0257 AC: 1067 AN: 41562

American (AMR) AF: 0.0361 AC: 553 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0766 AC: 266 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0312 AC: 150 AN: 4814

European-Finnish (FIN) AF: 0.0142 AC: 151 AN: 10614

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0497 AC: 3380 AN: 68012

Other (OTH) AF: 0.0501 AC: 106 AN: 2114

Alfa AF: 0.0394 Hom.: 87

Bravo AF: 0.0386

Asia WGS AF: 0.0140 AC: 47 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.4
DANN	Benign	0.65
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1225936; hg19: chr6-7885184;