GeneBe

NM_001365276.2:c.7440T>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001365276.2(TNXB):​c.7440T>A​(p.Tyr2480*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y2480Y) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TNXB
NM_001365276.2 stop_gained

Scores

2
1
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.50

Publications

25 publications found
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]
TNXB Gene-Disease associations (from GenCC):
  • Ehlers-Danlos syndrome
    Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
  • Ehlers-Danlos syndrome due to tenascin-X deficiency
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina, PanelApp Australia, Orphanet
  • familial vesicoureteral reflux
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • vesicoureteral reflux 8
    Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 rank MANE Protein UniProt
TNXBNM_001365276.2 linkc.7440T>A p.Tyr2480* stop_gained Exon 21 of 44 ENST00000644971.2 NP_001352205.1
TNXBNM_001428335.1 linkc.8181T>A p.Tyr2727* stop_gained Exon 22 of 45 NP_001415264.1
TNXBNM_019105.8 linkc.7440T>A p.Tyr2480* stop_gained Exon 21 of 44 NP_061978.6 P22105-1O95680Q9Y464O95681

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNXBENST00000644971.2 linkc.7440T>A p.Tyr2480* stop_gained Exon 21 of 44 NM_001365276.2 ENSP00000496448.1 P22105-3
TNXBENST00000647633.1 linkc.8181T>A p.Tyr2727* stop_gained Exon 22 of 45 ENSP00000497649.1 A0A3B3ISX9
TNXBENST00000375244.7 linkc.7440T>A p.Tyr2480* stop_gained Exon 21 of 44 5 ENSP00000364393.3 P22105-3

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD2 exomes
AF:
0.00000406
AC:
1
AN:
246578
AF XY:
0.00000745
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000900
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
6.84e-7
AC:
1
AN:
1461148
Hom.:
0
Cov.:
118
AF XY:
0.00000138
AC XY:
1
AN XY:
726898
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33308
American (AMR)
AF:
0.00
AC:
0
AN:
44710
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26118
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53142
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111796
Other (OTH)
AF:
0.00
AC:
0
AN:
60356
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
27
DANN
Uncertain
0.99
Eigen
Benign
-0.57
Eigen_PC
Benign
-0.93
FATHMM_MKL
Benign
0.11
N
PhyloP100
-3.5
Vest4
0.75
GERP RS
-4.8
Mutation Taster
=11/189
disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs204887; hg19: chr6-32029226; API