6-7888710-C-T

Variant names:

• chr6-7888710-C-T
• rs142322001
• NM_030810.5:c.958G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030810.5(TXNDC5):​c.958G>A​(p.Asp320Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,609,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TXNDC5 NM_030810.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0736427).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNDC5	NM_030810.5	MANE Select	c.958G>A	p.Asp320Asn	missense	Exon 7 of 10	NP_110437.2
	TXNDC5	NM_001145549.4		c.634G>A	p.Asp212Asn	missense	Exon 7 of 10	NP_001139021.1	Q8NBS9-2
	BLOC1S5-TXNDC5	NR_037616.1		n.1117G>A		non_coding_transcript_exon	Exon 10 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNDC5	ENST00000379757.9	TSL:1 MANE Select	c.958G>A	p.Asp320Asn	missense	Exon 7 of 10	ENSP00000369081.4	Q8NBS9-1
	TXNDC5	ENST00000473453.2	TSL:1	c.634G>A	p.Asp212Asn	missense	Exon 7 of 10	ENSP00000420784.1	Q8NBS9-2
	BLOC1S5-TXNDC5	ENST00000439343.2	TSL:2	n.*656G>A		non_coding_transcript_exon	Exon 10 of 13	ENSP00000454697.1	H3BN57

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1457704 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725082

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25948

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 85704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110740

Other (OTH) AF: 0.00 AC: 0 AN: 60266

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.77	N
PhyloP100		1.3
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.052
Sift	Benign	0.40	T
Sift4G	Benign	0.38	T
Polyphen		0.24	B
Vest4		0.22
MVP		0.081
MPC		0.13
ClinPred		0.043	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.47
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs142322001; hg19: chr6-7888943;