chr6-7889232-A-G

Variant names:

• chr6-7889232-A-G
• rs1225946
• NM_030810.5:c.819+263T>C

Variant summary

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

The NM_030810.5(TXNDC5):​c.819+263T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 467,516 control chromosomes in the GnomAD database, including 33,442 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 0.40 (13285 hom., cov: 33)
  • Exomes 𝑓: 0.33 (20157 hom.)
• Consequence: TXNDC5 NM_030810.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.515
• Publications: 1 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNDC5	NM_030810.5	c.819+263T>C		intron_variant	Intron 6 of 9	ENST00000379757.9	NP_110437.2
TXNDC5	NM_001145549.4	c.495+263T>C		intron_variant	Intron 6 of 9		NP_001139021.1
BLOC1S5-TXNDC5	NR_037616.1	n.978+263T>C		intron_variant	Intron 9 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNDC5	ENST00000379757.9	c.819+263T>C		intron_variant	Intron 6 of 9	1	NM_030810.5	ENSP00000369081.4
TXNDC5	ENST00000473453.2	c.495+263T>C		intron_variant	Intron 6 of 9	1		ENSP00000420784.1
BLOC1S5-TXNDC5	ENST00000439343.2	n.*517+263T>C		intron_variant	Intron 9 of 12	2		ENSP00000454697.1
TXNDC5	ENST00000460138.5	n.214T>C		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes AF: 0.395 AC: 59966 AN: 151900 Hom.: 13250 Cov.: 33

Gnomad AFR AF: 0.561

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.389

GnomAD4 exome AF: 0.332 AC: 104591 AN: 315500 Hom.: 20157 Cov.: 4 AF XY: 0.327 AC XY: 53470 AN XY: 163464

African (AFR) AF: 0.564 AC: 5510 AN: 9762

American (AMR) AF: 0.514 AC: 6409 AN: 12474

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 2458 AN: 10600

East Asian (EAS) AF: 0.692 AC: 16458 AN: 23778

South Asian (SAS) AF: 0.280 AC: 6102 AN: 21826

European-Finnish (FIN) AF: 0.264 AC: 5641 AN: 21362

Middle Eastern (MID) AF: 0.289 AC: 437 AN: 1512

European-Non Finnish (NFE) AF: 0.282 AC: 54956 AN: 194958

Other (OTH) AF: 0.344 AC: 6620 AN: 19228

GnomAD4 genome AF: 0.395 AC: 60054 AN: 152016 Hom.: 13285 Cov.: 33 AF XY: 0.396 AC XY: 29401 AN XY: 74292

African (AFR) AF: 0.561 AC: 23251 AN: 41438

American (AMR) AF: 0.485 AC: 7411 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 830 AN: 3468

East Asian (EAS) AF: 0.648 AC: 3351 AN: 5168

South Asian (SAS) AF: 0.303 AC: 1461 AN: 4814

European-Finnish (FIN) AF: 0.264 AC: 2794 AN: 10582

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19622 AN: 67954

Other (OTH) AF: 0.391 AC: 821 AN: 2102

Alfa AF: 0.324 Hom.: 9825

Bravo AF: 0.422

Asia WGS AF: 0.481 AC: 1672 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.6
DANN	Benign	0.71
PhyloP100		-0.52
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: rs1225946; hg19: chr6-7889465;