6-7888722-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000379757.9(TXNDC5):​c.946G>A​(p.Glu316Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,612,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TXNDC5
ENST00000379757.9 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.15
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.04610938).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TXNDC5NM_030810.5 linkuse as main transcriptc.946G>A p.Glu316Lys missense_variant 7/10 ENST00000379757.9 NP_110437.2
BLOC1S5-TXNDC5NR_037616.1 linkuse as main transcriptn.1105G>A non_coding_transcript_exon_variant 10/13
TXNDC5NM_001145549.4 linkuse as main transcriptc.622G>A p.Glu208Lys missense_variant 7/10 NP_001139021.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TXNDC5ENST00000379757.9 linkuse as main transcriptc.946G>A p.Glu316Lys missense_variant 7/101 NM_030810.5 ENSP00000369081 P1Q8NBS9-1
TXNDC5ENST00000473453.2 linkuse as main transcriptc.622G>A p.Glu208Lys missense_variant 7/101 ENSP00000420784 Q8NBS9-2
TXNDC5ENST00000460138.5 linkuse as main transcriptn.724G>A non_coding_transcript_exon_variant 1/42
TXNDC5ENST00000475802.1 linkuse as main transcriptn.240G>A non_coding_transcript_exon_variant 1/42

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152212
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000579
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000321
AC:
8
AN:
249326
Hom.:
0
AF XY:
0.0000297
AC XY:
4
AN XY:
134878
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000436
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1460242
Hom.:
0
Cov.:
31
AF XY:
0.00000964
AC XY:
7
AN XY:
726406
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152330
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000774
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ExAC
AF:
0.0000412
AC:
5
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

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 submitterclinical testingAmbry GeneticsMay 26, 2024The c.946G>A (p.E316K) alteration is located in exon 7 (coding exon 7) of the TXNDC5 gene. This alteration results from a G to A substitution at nucleotide position 946, causing the glutamic acid (E) at amino acid position 316 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
16
DANN
Benign
0.97
DEOGEN2
Benign
0.14
T;.
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.75
FATHMM_MKL
Benign
0.75
D
LIST_S2
Benign
0.82
T;T
M_CAP
Benign
0.0057
T
MetaRNN
Benign
0.046
T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
1.8
L;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-0.96
N;N
REVEL
Benign
0.045
Sift
Benign
0.38
T;T
Sift4G
Benign
0.34
T;T
Polyphen
0.36
B;.
Vest4
0.34
MutPred
0.49
Gain of ubiquitination at E316 (P = 0.0114);.;
MVP
0.067
MPC
0.14
ClinPred
0.036
T
GERP RS
2.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.13
gMVP
0.75

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs529416999; hg19: chr6-7888955; API