6-7883250-G-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_030810.5(TXNDC5):c.1193C>T(p.Thr398Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
TXNDC5
NM_030810.5 missense
NM_030810.5 missense
Scores
9
6
4
Clinical Significance
Conservation
PhyloP100: 6.65
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.977
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TXNDC5 | NM_030810.5 | c.1193C>T | p.Thr398Met | missense_variant | 10/10 | ENST00000379757.9 | NP_110437.2 | |
TXNDC5 | NM_001145549.4 | c.869C>T | p.Thr290Met | missense_variant | 10/10 | NP_001139021.1 | ||
BLOC1S5-TXNDC5 | NR_037616.1 | n.1352C>T | non_coding_transcript_exon_variant | 13/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TXNDC5 | ENST00000379757.9 | c.1193C>T | p.Thr398Met | missense_variant | 10/10 | 1 | NM_030810.5 | ENSP00000369081.4 | ||
BLOC1S5-TXNDC5 | ENST00000439343.2 | n.*891C>T | non_coding_transcript_exon_variant | 13/13 | 2 | ENSP00000454697.1 | ||||
BLOC1S5-TXNDC5 | ENST00000439343.2 | n.*891C>T | 3_prime_UTR_variant | 13/13 | 2 | ENSP00000454697.1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251078Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135758
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GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461860Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9AN XY: 727230
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74316
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 16, 2024 | The c.1193C>T (p.T398M) alteration is located in exon 10 (coding exon 10) of the TXNDC5 gene. This alteration results from a C to T substitution at nucleotide position 1193, causing the threonine (T) at amino acid position 398 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
H;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0752);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at