rs746016355

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001365276.2(TNXB):​c.4996C>T​(p.Arg1666Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,435,200 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 (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

TNXB
NM_001365276.2 stop_gained

Scores

2
2
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.88
Variant links:
Genes affected
TNXB (HGNC:11976): (tenascin XB) This gene encodes a member of the tenascin family of extracellular matrix glycoproteins. The tenascins have anti-adhesive effects, as opposed to fibronectin which is adhesive. This protein is thought to function in matrix maturation during wound healing, and its deficiency has been associated with the connective tissue disorder Ehlers-Danlos syndrome. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. It is one of four genes in this cluster which have been duplicated. The duplicated copy of this gene is incomplete and is a pseudogene which is transcribed but does not encode a protein. The structure of this gene is unusual in that it overlaps the CREBL1 and CYP21A2 genes at its 5' and 3' ends, respectively. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TNXBNM_001365276.2 linkuse as main transcriptc.4996C>T p.Arg1666Ter stop_gained 14/44 ENST00000644971.2 NP_001352205.1
TNXBNM_019105.8 linkuse as main transcriptc.4996C>T p.Arg1666Ter stop_gained 14/44 NP_061978.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TNXBENST00000644971.2 linkuse as main transcriptc.4996C>T p.Arg1666Ter stop_gained 14/44 NM_001365276.2 ENSP00000496448 P22105-3
TNXBENST00000647633.1 linkuse as main transcriptc.5737C>T p.Arg1913Ter stop_gained 15/45 ENSP00000497649 P1
TNXBENST00000375244.7 linkuse as main transcriptc.4996C>T p.Arg1666Ter stop_gained 14/445 ENSP00000364393 P22105-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000846
AC:
2
AN:
236470
Hom.:
0
AF XY:
0.0000154
AC XY:
2
AN XY:
129504
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000338
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000941
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000348
AC:
5
AN:
1435200
Hom.:
0
Cov.:
31
AF XY:
0.00000422
AC XY:
3
AN XY:
710340
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000510
Gnomad4 SAS exome
AF:
0.0000119
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000182
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000829
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome due to tenascin-X deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 16, 2014The p.Arg1666X variant in TNXB has not been previously reported in the literature but has been identified in 1/13218 South Asian chromosomes by the Exome Aggregation Consortium (ExAC) (http://exac.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1666, which is predicted to lead to a truncated or absent protein. Complete loss of TNXB function has been described in a few families with Ehlers-Danlos-like syndrome (Schalkwijk 2001, Merke 2013, Penisson-Besnier 2013) and a TNXB mouse knockout model indicates that complete loss of TNXB function results in abnormal collagen deposition (Mao 2002). In summary, while there is some suspicion for a pathogenic role of loss-of-function TNXB variants in Ehlers-Danlos-like syndrome, the clinical significance of the p.Arg1666X variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
36
DANN
Uncertain
1.0
Eigen
Uncertain
0.26
Eigen_PC
Benign
-0.045
FATHMM_MKL
Benign
0.11
N
MutationTaster
Benign
1.0
A;A
Vest4
0.67
GERP RS
2.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs746016355; hg19: chr6-32038186; COSMIC: COSV64480631; API