rs1225944

chr6-7888855-A-Gchr6-7888855-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.820-7T>C variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005265
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.506

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=-0.94).
• 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/exons	MANE	UniProt
TXNDC5	NM_030810.5	c.820-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000379757.9
BLOC1S5-TXNDC5	NR_037616.1	n.979-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant
TXNDC5	NM_001145549.4	c.496-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNDC5	ENST00000379757.9	c.820-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_030810.5	P1
TXNDC5	ENST00000473453.2	c.496-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
TXNDC5	ENST00000460138.5	n.591T>C		non_coding_transcript_exon_variant	1/4	2
TXNDC5	ENST00000475802.1	n.107T>C		non_coding_transcript_exon_variant	1/4	2

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

GnomAD3 exomes AF: 0.486 AC: 116413 AN: 239360 Hom.: 31701 AF XY: 0.466 AC XY: 60279 AN XY: 129280

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 SAS exome AF: 0.399

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

Gnomad4 AFR exome AF: 0.835

Gnomad4 AMR exome AF: 0.678

Gnomad4 ASJ exome AF: 0.316

Gnomad4 EAS exome AF: 0.781

Gnomad4 SAS exome AF: 0.400

Gnomad4 FIN exome AF: 0.425

Gnomad4 NFE exome AF: 0.382

Gnomad4 OTH exome AF: 0.441

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

Gnomad4 AFR AF: 0.818

Gnomad4 AMR AF: 0.588

Gnomad4 ASJ AF: 0.312

Gnomad4 EAS AF: 0.764

Gnomad4 SAS AF: 0.410

Gnomad4 FIN AF: 0.431

Gnomad4 NFE AF: 0.384

Gnomad4 OTH AF: 0.512

Alfa AF: 0.466 Hom.: 8142

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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1225944; hg19: chr6-7889088;