chr6-7883245-A-C

Variant names:

• chr6-7883245-A-C
• rs201450918
• NM_030810.5:c.1198T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_030810.5(TXNDC5):​c.1198T>G​(p.Leu400Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TXNDC5 NM_030810.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.130
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3064471).

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.1198T>G	p.Leu400Val	missense	Exon 10 of 10	NP_110437.2
	TXNDC5	NM_001145549.4		c.874T>G	p.Leu292Val	missense	Exon 10 of 10	NP_001139021.1	Q8NBS9-2
	BLOC1S5-TXNDC5	NR_037616.1		n.1357T>G		non_coding_transcript_exon	Exon 13 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNDC5	ENST00000379757.9	TSL:1 MANE Select	c.1198T>G	p.Leu400Val	missense	Exon 10 of 10	ENSP00000369081.4	Q8NBS9-1
	TXNDC5	ENST00000473453.2	TSL:1	c.874T>G	p.Leu292Val	missense	Exon 10 of 10	ENSP00000420784.1	Q8NBS9-2
	BLOC1S5-TXNDC5	ENST00000439343.2	TSL:2	n.*896T>G		non_coding_transcript_exon	Exon 13 of 13	ENSP00000454697.1	H3BN57

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 33

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	0.097
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.2
DANN	Uncertain	0.98
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.13
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.10
Sift	Benign	0.11	T
Sift4G	Benign	0.18	T
Polyphen		0.056	B
Vest4		0.34
MutPred		0.59		Gain of MoRF binding (P = 0.0737)
MVP		0.099
MPC		0.22
ClinPred		0.31	T
GERP RS		-0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.77
Mutation Taster		=60/40	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: rs201450918; hg19: chr6-7883478;