rs774675861
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001365276.2(TNXB):āc.697T>Gā(p.Cys233Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,448,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 10/17 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0000014 ( 0 hom. )
Consequence
TNXB
NM_001365276.2 missense
NM_001365276.2 missense
Scores
12
4
2
Clinical Significance
Conservation
PhyloP100: 4.35
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.962
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNXB | NM_001365276.2 | c.697T>G | p.Cys233Gly | missense_variant | 3/44 | ENST00000644971.2 | |
TNXB | NM_019105.8 | c.697T>G | p.Cys233Gly | missense_variant | 3/44 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNXB | ENST00000644971.2 | c.697T>G | p.Cys233Gly | missense_variant | 3/44 | NM_001365276.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000910 AC: 2AN: 219784Hom.: 0 AF XY: 0.00000835 AC XY: 1AN XY: 119752
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GnomAD4 exome AF: 0.00000138 AC: 2AN: 1448354Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1AN XY: 719442
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GnomAD4 genome Cov.: 33
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33
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 08, 2017 | Lines of evidence used in support of classification: CANDIDATE: Alteration(s) of Potential Clinical Relevance Detected - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;D;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Pathogenic
.;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;.;D;.;D
REVEL
Pathogenic
Sift
Pathogenic
.;.;D;.;D
Sift4G
Uncertain
.;.;D;D;D
Vest4
0.66, 0.81
MutPred
Gain of catalytic residue at V234 (P = 0.0901);Gain of catalytic residue at V234 (P = 0.0901);Gain of catalytic residue at V234 (P = 0.0901);Gain of catalytic residue at V234 (P = 0.0901);Gain of catalytic residue at V234 (P = 0.0901);
MVP
0.99
ClinPred
D
GERP RS
Varity_R
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at