rs3734589

Variant names:

• chr6-7891542-G-A
• rs3734589
• NM_030810.5:c.732+79C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_030810.5(TXNDC5):​c.732+79C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0987 in 1,177,970 control chromosomes in the GnomAD database, including 6,058 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 0.11 (979 hom., cov: 33)
  • Exomes 𝑓: 0.097 (5079 hom.)
• Consequence: TXNDC5 NM_030810.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0490
• Publications: 8 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=-0.66).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030810.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNDC5	NM_030810.5	MANE Select	c.732+79C>T		intron	N/A	NP_110437.2
	TXNDC5	NM_001145549.4		c.408+79C>T		intron	N/A	NP_001139021.1	Q8NBS9-2
	BLOC1S5-TXNDC5	NR_037616.1		n.891+79C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNDC5	ENST00000379757.9	TSL:1 MANE Select	c.732+79C>T		intron	N/A	ENSP00000369081.4	Q8NBS9-1
	TXNDC5	ENST00000473453.2	TSL:1	c.408+79C>T		intron	N/A	ENSP00000420784.1	Q8NBS9-2
	BLOC1S5-TXNDC5	ENST00000439343.2	TSL:2	n.*430+79C>T		intron	N/A	ENSP00000454697.1	H3BN57

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16840 AN: 152090 Hom.: 975 Cov.: 33

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.0823

Gnomad ASJ AF: 0.0689

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.0929

Gnomad NFE AF: 0.0939

Gnomad OTH AF: 0.0933

GnomAD4 exome AF: 0.0969 AC: 99397 AN: 1025760 Hom.: 5079 AF XY: 0.0970 AC XY: 50133 AN XY: 516856

African (AFR) AF: 0.147 AC: 3489 AN: 23794

American (AMR) AF: 0.101 AC: 3224 AN: 32062

Ashkenazi Jewish (ASJ) AF: 0.0714 AC: 1501 AN: 21014

East Asian (EAS) AF: 0.0981 AC: 3495 AN: 35642

South Asian (SAS) AF: 0.105 AC: 6923 AN: 66198

European-Finnish (FIN) AF: 0.153 AC: 7728 AN: 50574

Middle Eastern (MID) AF: 0.0900 AC: 358 AN: 3978

European-Non Finnish (NFE) AF: 0.0914 AC: 68308 AN: 747648

Other (OTH) AF: 0.0975 AC: 4371 AN: 44850

GnomAD4 genome AF: 0.111 AC: 16866 AN: 152210 Hom.: 979 Cov.: 33 AF XY: 0.114 AC XY: 8501 AN XY: 74422

African (AFR) AF: 0.140 AC: 5796 AN: 41516

American (AMR) AF: 0.0823 AC: 1258 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0689 AC: 239 AN: 3470

East Asian (EAS) AF: 0.115 AC: 595 AN: 5182

South Asian (SAS) AF: 0.106 AC: 513 AN: 4828

European-Finnish (FIN) AF: 0.168 AC: 1779 AN: 10594

Middle Eastern (MID) AF: 0.0993 AC: 29 AN: 292

European-Non Finnish (NFE) AF: 0.0939 AC: 6386 AN: 68014

Other (OTH) AF: 0.0971 AC: 205 AN: 2112

Alfa AF: 0.105 Hom.: 200

Bravo AF: 0.108

Asia WGS AF: 0.137 AC: 477 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	3.2
DANN	Benign	0.80
PhyloP100		0.049
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3734589;

hg19: chr6-7891775;

COSMIC: COSV65730409;

COSMIC: COSV65730409;