rs9502658

chr6-7891714-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BS1 BS2

The NM_030810.5(TXNDC5):c.639C>T(p.Phe213=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,613,654 control chromosomes in the GnomAD database, including 71 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 0.012 (36 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (35 hom.)
• Consequence: TXNDC5 NM_030810.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.73

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP7: Synonymous conserved (PhyloP=1.73 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0122 (1865/152306) while in subpopulation AFR AF= 0.0418 (1737/41542). AF 95% confidence interval is 0.0402. There are 36 homozygotes in gnomad4. There are 899 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TXNDC5	NM_030810.5	c.639C>T	p.Phe213=	synonymous_variant	5/10	ENST00000379757.9
BLOC1S5-TXNDC5	NR_037616.1	n.798C>T		non_coding_transcript_exon_variant	8/13
TXNDC5	NM_001145549.4	c.315C>T	p.Phe105=	synonymous_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNDC5	ENST00000379757.9	c.639C>T	p.Phe213=	synonymous_variant	5/10	1	NM_030810.5	P1
TXNDC5	ENST00000473453.2	c.315C>T	p.Phe105=	synonymous_variant	5/10	1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1866 AN: 152188 Hom.: 36 Cov.: 33

Gnomad AFR AF: 0.0420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00287 AC: 722 AN: 251152 Hom.: 14 AF XY: 0.00200 AC XY: 271 AN XY: 135772

Gnomad AFR exome AF: 0.0403

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00122 AC: 1789 AN: 1461348 Hom.: 35 Cov.: 30 AF XY: 0.000990 AC XY: 720 AN XY: 726986

Gnomad4 AFR exome AF: 0.0456

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.0122 AC: 1865 AN: 152306 Hom.: 36 Cov.: 33 AF XY: 0.0121 AC XY: 899 AN XY: 74480

Gnomad4 AFR AF: 0.0418

Gnomad4 AMR AF: 0.00653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00501 Hom.: 14

Bravo AF: 0.0135

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	12
Dann	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs9502658; hg19: chr6-7891947;