rs1225938

Variant names:

• chr6-7886301-C-T
• rs1225938
• NM_030810.5:c.964-258G>A

Variant summary

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

The NM_030810.5(TXNDC5):​c.964-258G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 151,838 control chromosomes in the GnomAD database, including 10,566 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 0.36 (10566 hom., cov: 31)
• Consequence: TXNDC5 NM_030810.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.63 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNDC5	NM_030810.5	MANE Select	c.964-258G>A		intron	N/A	NP_110437.2
	TXNDC5	NM_001145549.4		c.640-258G>A		intron	N/A	NP_001139021.1
	BLOC1S5-TXNDC5	NR_037616.1		n.1123-258G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNDC5	ENST00000379757.9	TSL:1 MANE Select	c.964-258G>A		intron	N/A	ENSP00000369081.4
	TXNDC5	ENST00000473453.2	TSL:1	c.640-258G>A		intron	N/A	ENSP00000420784.1
	BLOC1S5-TXNDC5	ENST00000439343.2	TSL:2	n.*662-258G>A		intron	N/A	ENSP00000454697.1

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54577 AN: 151720 Hom.: 10545 Cov.: 31

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.360

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

GnomAD4 genome AF: 0.360 AC: 54639 AN: 151838 Hom.: 10566 Cov.: 31 AF XY: 0.361 AC XY: 26811 AN XY: 74210

African (AFR) AF: 0.443 AC: 18321 AN: 41360

American (AMR) AF: 0.468 AC: 7146 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 825 AN: 3468

East Asian (EAS) AF: 0.649 AC: 3333 AN: 5138

South Asian (SAS) AF: 0.301 AC: 1448 AN: 4816

European-Finnish (FIN) AF: 0.263 AC: 2772 AN: 10544

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.287 AC: 19523 AN: 67930

Other (OTH) AF: 0.362 AC: 764 AN: 2110

Alfa AF: 0.314 Hom.: 987

Bravo AF: 0.383

Asia WGS AF: 0.468 AC: 1627 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.70
DANN	Benign	0.56
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs1225938; hg19: chr6-7886534;