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
Consequence
NM_001365276.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TNXB | NM_001365276.2 | c.4996C>T | p.Arg1666Ter | stop_gained | 14/44 | ENST00000644971.2 | NP_001352205.1 | |
TNXB | NM_019105.8 | c.4996C>T | p.Arg1666Ter | stop_gained | 14/44 | NP_061978.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TNXB | ENST00000644971.2 | c.4996C>T | p.Arg1666Ter | stop_gained | 14/44 | NM_001365276.2 | ENSP00000496448 | |||
TNXB | ENST00000647633.1 | c.5737C>T | p.Arg1913Ter | stop_gained | 15/45 | ENSP00000497649 | P1 | |||
TNXB | ENST00000375244.7 | c.4996C>T | p.Arg1666Ter | stop_gained | 14/44 | 5 | ENSP00000364393 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000846 AC: 2AN: 236470Hom.: 0 AF XY: 0.0000154 AC XY: 2AN XY: 129504
GnomAD4 exome AF: 0.00000348 AC: 5AN: 1435200Hom.: 0 Cov.: 31 AF XY: 0.00000422 AC XY: 3AN XY: 710340
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome due to tenascin-X deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 16, 2014 | The 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at