chr6-7889233-A-G

Variant names:

• chr6-7889233-A-G
• rs7746818
• NM_030810.5:c.819+262T>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+262T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 472,336 control chromosomes in the GnomAD database, including 156 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 0.028 (86 hom., cov: 33)
  • Exomes 𝑓: 0.016 (70 hom.)
• Consequence: TXNDC5 NM_030810.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.101
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNDC5	NM_030810.5	c.819+262T>C		intron_variant	Intron 6 of 9	ENST00000379757.9	NP_110437.2
TXNDC5	NM_001145549.4	c.495+262T>C		intron_variant	Intron 6 of 9		NP_001139021.1
BLOC1S5-TXNDC5	NR_037616.1	n.978+262T>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+262T>C		intron_variant	Intron 6 of 9	1	NM_030810.5	ENSP00000369081.4
TXNDC5	ENST00000473453.2	c.495+262T>C		intron_variant	Intron 6 of 9	1		ENSP00000420784.1
BLOC1S5-TXNDC5	ENST00000439343.2	n.*517+262T>C		intron_variant	Intron 9 of 12	2		ENSP00000454697.1
TXNDC5	ENST00000460138.5	n.213T>C		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 4281 AN: 152158 Hom.: 84 Cov.: 33

Gnomad AFR AF: 0.0605

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0240

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0268

GnomAD4 exome AF: 0.0158 AC: 5061 AN: 320060 Hom.: 70 Cov.: 4 AF XY: 0.0157 AC XY: 2607 AN XY: 165870

African (AFR) AF: 0.0632 AC: 628 AN: 9934

American (AMR) AF: 0.0169 AC: 217 AN: 12854

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 198 AN: 10718

East Asian (EAS) AF: 0.0000413 AC: 1 AN: 24232

South Asian (SAS) AF: 0.00659 AC: 149 AN: 22600

European-Finnish (FIN) AF: 0.00861 AC: 186 AN: 21610

Middle Eastern (MID) AF: 0.0172 AC: 26 AN: 1516

European-Non Finnish (NFE) AF: 0.0168 AC: 3305 AN: 197060

Other (OTH) AF: 0.0180 AC: 351 AN: 19536

GnomAD4 genome AF: 0.0282 AC: 4292 AN: 152276 Hom.: 86 Cov.: 33 AF XY: 0.0276 AC XY: 2058 AN XY: 74460

African (AFR) AF: 0.0605 AC: 2514 AN: 41540

American (AMR) AF: 0.0241 AC: 368 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4824

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10618

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0173 AC: 1179 AN: 68032

Other (OTH) AF: 0.0255 AC: 54 AN: 2114

Alfa AF: 0.0226 Hom.: 11

Bravo AF: 0.0302

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.63
PhyloP100		-0.10
Mutation Taster		=100/0	polymorphism

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: rs7746818; hg19: chr6-7889466;