6-7888855-A-G

Variant names:

• chr6-7888855-A-G
• rs1225944
• NM_030810.5:c.820-7T>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.820-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,599,936 control chromosomes in the GnomAD database, including 159,072 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.54 (25217 hom., cov: 33)
  • Exomes 𝑓: 0.42 (133855 hom.)
• Consequence: TXNDC5 NM_030810.5 splice_region, intron
• Scores: Splicing: ADA: 0.00005265
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.506
• Publications: 15 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNDC5	NM_030810.5	c.820-7T>C		splice_region_variant, intron_variant	Intron 6 of 9	ENST00000379757.9	NP_110437.2
TXNDC5	NM_001145549.4	c.496-7T>C		splice_region_variant, intron_variant	Intron 6 of 9		NP_001139021.1
BLOC1S5-TXNDC5	NR_037616.1	n.979-7T>C		splice_region_variant, intron_variant	Intron 9 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNDC5	ENST00000379757.9	c.820-7T>C		splice_region_variant, intron_variant	Intron 6 of 9	1	NM_030810.5	ENSP00000369081.4
BLOC1S5-TXNDC5	ENST00000439343.2	n.*518-7T>C		splice_region_variant, intron_variant	Intron 9 of 12	2		ENSP00000454697.1

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82239 AN: 152074 Hom.: 25151 Cov.: 33

Gnomad AFR AF: 0.818

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.588

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.764

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.507

GnomAD2 exomes AF: 0.486 AC: 116413 AN: 239360 AF XY: 0.466

Gnomad AFR exome AF: 0.831

Gnomad AMR exome AF: 0.695

Gnomad ASJ exome AF: 0.316

Gnomad EAS exome AF: 0.758

Gnomad FIN exome AF: 0.437

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.425

GnomAD4 exome AF: 0.416 AC: 601946 AN: 1447744 Hom.: 133855 Cov.: 42 AF XY: 0.412 AC XY: 296473 AN XY: 719060

African (AFR) AF: 0.835 AC: 27438 AN: 32844

American (AMR) AF: 0.678 AC: 29038 AN: 42856

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 8048 AN: 25464

East Asian (EAS) AF: 0.781 AC: 30491 AN: 39042

South Asian (SAS) AF: 0.400 AC: 33627 AN: 84104

European-Finnish (FIN) AF: 0.425 AC: 22582 AN: 53128

Middle Eastern (MID) AF: 0.394 AC: 2256 AN: 5724

European-Non Finnish (NFE) AF: 0.382 AC: 422138 AN: 1104842

Other (OTH) AF: 0.441 AC: 26328 AN: 59740

GnomAD4 genome AF: 0.541 AC: 82369 AN: 152192 Hom.: 25217 Cov.: 33 AF XY: 0.544 AC XY: 40492 AN XY: 74384

African (AFR) AF: 0.818 AC: 34010 AN: 41556

American (AMR) AF: 0.588 AC: 8993 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1083 AN: 3466

East Asian (EAS) AF: 0.764 AC: 3952 AN: 5170

South Asian (SAS) AF: 0.410 AC: 1975 AN: 4816

European-Finnish (FIN) AF: 0.431 AC: 4557 AN: 10564

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.384 AC: 26105 AN: 68010

Other (OTH) AF: 0.512 AC: 1081 AN: 2110

Alfa AF: 0.470 Hom.: 8406

Bravo AF: 0.570

Asia WGS AF: 0.629 AC: 2186 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.17
DANN	Benign	0.38
PhyloP100		-0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000053
dbscSNV1_RF	Benign	0.058
SpliceAI score (max)		0.010		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: rs1225944; hg19: chr6-7889088; COSMIC: COSV107490765;