rs1225946

Positions:

• chr6-7889232-A-G
• chr6-7889232-A-T

Variant summary

Our verdict is Benign. Variant got -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

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:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
TXNDC5	NM_030810.5	c.819+263T>C		intron_variant		ENST00000379757.9	NP_110437.2
BLOC1S5-TXNDC5	NR_037616.1	n.978+263T>C		intron_variant, non_coding_transcript_variant
TXNDC5	NM_001145549.4	c.495+263T>C		intron_variant			NP_001139021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNDC5	ENST00000379757.9	c.819+263T>C		intron_variant		1	NM_030810.5	ENSP00000369081	P1
TXNDC5	ENST00000473453.2	c.495+263T>C		intron_variant		1		ENSP00000420784
TXNDC5	ENST00000460138.5	n.214T>C		non_coding_transcript_exon_variant	1/4	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

Gnomad4 AFR exome AF: 0.564

Gnomad4 AMR exome AF: 0.514

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.692

Gnomad4 SAS exome AF: 0.280

Gnomad4 FIN exome AF: 0.264

Gnomad4 NFE exome AF: 0.282

Gnomad4 OTH exome AF: 0.344

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

Gnomad4 AFR AF: 0.561

Gnomad4 AMR AF: 0.485

Gnomad4 ASJ AF: 0.239

Gnomad4 EAS AF: 0.648

Gnomad4 SAS AF: 0.303

Gnomad4 FIN AF: 0.264

Gnomad4 NFE AF: 0.289

Gnomad4 OTH AF: 0.391

Alfa AF: 0.320 Hom.: 7814

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1225946; hg19: chr6-7889465;