GeneBe

chr6-32067852-GGGAC-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001428335.1(TNXB):​c.7090_7093delGTCC​(p.Val2364ProfsTer80) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TNXB
NM_001428335.1 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 3.40

Publications

0 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 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;
PP5
Variant 6-32067852-GGGAC-G is Pathogenic according to our data. Variant chr6-32067852-GGGAC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 523526.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001428335.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
TNXB
NM_001365276.2
MANE Select
c.6349_6352delGTCCp.Val2117ProfsTer80
frameshift
Exon 18 of 44NP_001352205.1
TNXB
NM_001428335.1
c.7090_7093delGTCCp.Val2364ProfsTer80
frameshift
Exon 19 of 45NP_001415264.1
TNXB
NM_019105.8
c.6349_6352delGTCCp.Val2117ProfsTer80
frameshift
Exon 18 of 44NP_061978.6

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
TNXB
ENST00000644971.2
MANE Select
c.6349_6352delGTCCp.Val2117ProfsTer80
frameshift
Exon 18 of 44ENSP00000496448.1
TNXB
ENST00000647633.1
c.7090_7093delGTCCp.Val2364ProfsTer80
frameshift
Exon 19 of 45ENSP00000497649.1
TNXB
ENST00000375244.7
TSL:5
c.6349_6352delGTCCp.Val2117ProfsTer80
frameshift
Exon 18 of 44ENSP00000364393.3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152214
Hom.:
0
Cov.:
32
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000121
AC:
3
AN:
247316
AF XY:
0.0000149
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:
0.0000268
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000342
AC:
5
AN:
1460740
Hom.:
0
AF XY:
0.00000275
AC XY:
2
AN XY:
726658
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33468
American (AMR)
AF:
0.00
AC:
0
AN:
44724
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:
86222
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53230
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5108
European-Non Finnish (NFE)
AF:
0.00000450
AC:
5
AN:
1111862
Other (OTH)
AF:
0.00
AC:
0
AN:
60290
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.455
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152214
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74360
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41436
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10632
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68042
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

ClinVar submissions as Germline
Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
1
-
Cyanosis;C0013404:Dyspnea;C0026827:Hypotonia;C0027066:Myoclonus;C1837388:Abnormal pattern of respiration;C3806216:Neonatal breathing dysregulation;C3808046:Breathing dysregulation (1)
1
-
-
Ehlers-Danlos syndrome due to tenascin-X deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
3.4
Mutation Taster
=17/183
disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs754439905; hg19: chr6-32035629; API