rs9502656

Positions:

• chr6-7883153-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The ENST00000379757.9(TXNDC5):​c.1290C>T​(p.Asp430=) 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 ENST00000379757.9 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.768

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:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
TXNDC5	NM_030810.5	c.1290C>T	p.Asp430=	synonymous_variant	10/10	ENST00000379757.9	NP_110437.2
BLOC1S5-TXNDC5	NR_037616.1	n.1449C>T		non_coding_transcript_exon_variant	13/13
TXNDC5	NM_001145549.4	c.966C>T	p.Asp322=	synonymous_variant	10/10		NP_001139021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNDC5	ENST00000379757.9	c.1290C>T	p.Asp430=	synonymous_variant	10/10	1	NM_030810.5	ENSP00000369081	P1
TXNDC5	ENST00000473453.2	c.966C>T	p.Asp322=	synonymous_variant	10/10	1		ENSP00000420784
TXNDC5	ENST00000460138.5	n.1068C>T		non_coding_transcript_exon_variant	4/4	2
TXNDC5	ENST00000475802.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0736 AC: 11193 AN: 152106 Hom.: 1003 Cov.: 32

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

GnomAD3 exomes AF: 0.0295 AC: 7429 AN: 251442 Hom.: 431 AF XY: 0.0252 AC XY: 3423 AN XY: 135898

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 SAS exome AF: 0.00679

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.: 30 AF XY: 0.0222 AC XY: 16137 AN XY: 727234

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.0269

Gnomad4 ASJ exome AF: 0.0250

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00777

Gnomad4 FIN exome AF: 0.00753

Gnomad4 NFE exome AF: 0.0193

Gnomad4 OTH exome AF: 0.0298

GnomAD4 genome AF: 0.0736 AC: 11208 AN: 152224 Hom.: 1003 Cov.: 32 AF XY: 0.0723 AC XY: 5381 AN XY: 74436

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.0466

Gnomad4 ASJ AF: 0.0280

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.00593

Gnomad4 NFE AF: 0.0187

Gnomad4 OTH AF: 0.0602

Alfa AF: 0.0458 Hom.: 275

Bravo AF: 0.0828

Asia WGS AF: 0.0150 AC: 54 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
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs9502656; hg19: chr6-7883386;