chr6-7884419-C-T

Variant names:

• chr6-7884419-C-T
• rs2277105
• NM_030810.5:c.1116G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_030810.5(TXNDC5):​c.1116G>A​(p.Ala372Ala) 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
• Publications: 8 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 -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030810.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNDC5	NM_030810.5	MANE Select	c.1116G>A	p.Ala372Ala	synonymous	Exon 9 of 10	NP_110437.2
	TXNDC5	NM_001145549.4		c.792G>A	p.Ala264Ala	synonymous	Exon 9 of 10	NP_001139021.1
	BLOC1S5-TXNDC5	NR_037616.1		n.1275G>A		non_coding_transcript_exon	Exon 12 of 13

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNDC5	ENST00000379757.9	TSL:1 MANE Select	c.1116G>A	p.Ala372Ala	synonymous	Exon 9 of 10	ENSP00000369081.4
	TXNDC5	ENST00000473453.2	TSL:1	c.792G>A	p.Ala264Ala	synonymous	Exon 9 of 10	ENSP00000420784.1
	BLOC1S5-TXNDC5	ENST00000439343.2	TSL:2	n.*814G>A		non_coding_transcript_exon	Exon 12 of 13	ENSP00000454697.1

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

GnomAD2 exomes AF: 0.0312 AC: 7849 AN: 251494 AF XY: 0.0261

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 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

African (AFR) AF: 0.00206 AC: 69 AN: 33480

American (AMR) AF: 0.129 AC: 5760 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.123 AC: 4889 AN: 39690

South Asian (SAS) AF: 0.00441 AC: 380 AN: 86258

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53420

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.00174 AC: 1930 AN: 1111992

Other (OTH) AF: 0.0124 AC: 746 AN: 60396

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

African (AFR) AF: 0.00279 AC: 116 AN: 41546

American (AMR) AF: 0.0868 AC: 1326 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.145 AC: 749 AN: 5174

South Asian (SAS) AF: 0.00953 AC: 46 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00207 AC: 141 AN: 68002

Other (OTH) AF: 0.0227 AC: 48 AN: 2110

Alfa AF: 0.00827 Hom.: 87

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.6
DANN	Benign	0.88
PhyloP100		-0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2277105; hg19: chr6-7884652; COSMIC: COSV51660422; COSMIC: COSV51660422;