rs2277105

chr6-7884419-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_030810.5(TXNDC5):c.1116G>A(p.Ala372=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,614,088 control chromosomes in the GnomAD database, including 910 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 0.016 (151 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (759 hom.)
• Consequence: TXNDC5 NM_030810.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.888

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP7: Synonymous conserved (PhyloP=-0.888 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TXNDC5	NM_030810.5	c.1116G>A	p.Ala372=	synonymous_variant	9/10	ENST00000379757.9
BLOC1S5-TXNDC5	NR_037616.1	n.1275G>A		non_coding_transcript_exon_variant	12/13
TXNDC5	NM_001145549.4	c.792G>A	p.Ala264=	synonymous_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNDC5	ENST00000379757.9	c.1116G>A	p.Ala372=	synonymous_variant	9/10	1	NM_030810.5	P1
TXNDC5	ENST00000473453.2	c.792G>A	p.Ala264=	synonymous_variant	9/10	1
TXNDC5	ENST00000460138.5	n.894G>A		non_coding_transcript_exon_variant	3/4	2
TXNDC5	ENST00000475802.1	n.410G>A		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2439 AN: 152106 Hom.: 150 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0864

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.00932

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0312 AC: 7849 AN: 251494 Hom.: 557 AF XY: 0.0261 AC XY: 3551 AN XY: 135920

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.133

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.149

Gnomad SAS exome AF: 0.00431

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.0249

GnomAD4 exome AF: 0.00945 AC: 13812 AN: 1461864 Hom.: 759 Cov.: 30 AF XY: 0.00877 AC XY: 6380 AN XY: 727232

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.129

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.00441

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.00174

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome AF: 0.0161 AC: 2449 AN: 152224 Hom.: 151 Cov.: 32 AF XY: 0.0183 AC XY: 1364 AN XY: 74440

Gnomad4 AFR AF: 0.00279

Gnomad4 AMR AF: 0.0868

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.00953

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00207

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.00653 Hom.: 52

Bravo AF: 0.0240

Asia WGS AF: 0.0580 AC: 201 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00154

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	5.6
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2277105; hg19: chr6-7884652; COSMIC: COSV51660422; COSMIC: COSV51660422;