chr6-32084637-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001365276.2(TNXB):​c.3221C>A​(p.Thr1074Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,447,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.38

Publications

1 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: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.35983527).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TNXBNM_001365276.2 linkc.3221C>A p.Thr1074Asn missense_variant Exon 8 of 44 ENST00000644971.2 NP_001352205.1
TNXBNM_001428335.1 linkc.3962C>A p.Thr1321Asn missense_variant Exon 9 of 45 NP_001415264.1
TNXBNM_019105.8 linkc.3221C>A p.Thr1074Asn missense_variant Exon 8 of 44 NP_061978.6 P22105-1O95680Q9Y464O95681

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNXBENST00000644971.2 linkc.3221C>A p.Thr1074Asn missense_variant Exon 8 of 44 NM_001365276.2 ENSP00000496448.1 P22105-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000207
AC:
3
AN:
1447876
Hom.:
0
Cov.:
31
AF XY:
0.00000278
AC XY:
2
AN XY:
718554
show subpopulations
African (AFR)
AF:
0.0000899
AC:
3
AN:
33354
American (AMR)
AF:
0.00
AC:
0
AN:
44380
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25932
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39494
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84352
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49346
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5736
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1105442
Other (OTH)
AF:
0.00
AC:
0
AN:
59840
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
1
1
2
2
3
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.:
32
Alfa
AF:
0.00
Hom.:
0

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Jan 02, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.068
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.34
T;.;T;.
Eigen
Benign
0.18
Eigen_PC
Benign
-0.028
FATHMM_MKL
Benign
0.16
N
LIST_S2
Benign
0.61
.;T;T;D
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.36
T;T;T;T
MetaSVM
Benign
-0.77
T
PhyloP100
1.4
PrimateAI
Benign
0.37
T
PROVEAN
Uncertain
-3.4
.;.;D;.
REVEL
Benign
0.25
Sift
Uncertain
0.0070
.;.;D;.
Sift4G
Uncertain
0.012
.;.;D;D
Vest4
0.40
MutPred
0.60
Loss of phosphorylation at T1074 (P = 0.0159);.;Loss of phosphorylation at T1074 (P = 0.0159);.;
MVP
0.44
ClinPred
0.91
D
GERP RS
4.1
Varity_R
0.42
Mutation Taster
=94/6
polymorphism

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: rs867358435; hg19: chr6-32052414; API