6-32097988-C-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_001365276.2(TNXB):c.211G>T(p.Val71Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,607,206 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001365276.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TNXB | NM_001365276.2 | c.211G>T | p.Val71Leu | missense_variant | Exon 2 of 44 | ENST00000644971.2 | NP_001352205.1 | |
TNXB | NM_001428335.1 | c.211G>T | p.Val71Leu | missense_variant | Exon 2 of 45 | NP_001415264.1 | ||
TNXB | NM_019105.8 | c.211G>T | p.Val71Leu | missense_variant | Exon 2 of 44 | NP_061978.6 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000289 AC: 44AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000261 AC: 65AN: 248886Hom.: 0 AF XY: 0.000237 AC XY: 32AN XY: 135070
GnomAD4 exome AF: 0.000300 AC: 437AN: 1455002Hom.: 1 Cov.: 32 AF XY: 0.000303 AC XY: 219AN XY: 723406
GnomAD4 genome AF: 0.000289 AC: 44AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17AN XY: 74360
ClinVar
Submissions by phenotype
not provided Uncertain:5
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 71 of the TNXB protein (p.Val71Leu). This variant is present in population databases (rs201922477, gnomAD 0.05%). This missense change has been observed in individual(s) with vesicoureteral reflux (PMID: 26408188). ClinVar contains an entry for this variant (Variation ID: 289817). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
TNXB: PM2 -
Reported in a family in which two individuals were reported to be heterozygous for the variant; one patient with joint hypermobility and the other patient with bilateral vesicoureteral reflux (PMID: 26408188); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 26408188) -
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Ehlers-Danlos syndrome due to tenascin-X deficiency Uncertain:1
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TNXB-related disorder Uncertain:1
The TNXB c.211G>T variant is predicted to result in the amino acid substitution p.Val71Leu. This variant has been reported in an individual with vesicoureteral reflux (Elahi et al. 2016. PubMed ID: 26408188). This variant is reported in 0.056% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Ehlers-Danlos syndrome due to tenascin-X deficiency;C4014831:Vesicoureteral reflux 8 Uncertain:1
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Cardiovascular phenotype Uncertain:1
The p.V71L variant (also known as c.211G>T), located in coding exon 1 of the TNXB gene, results from a G to T substitution at nucleotide position 211. The valine at codon 71 is replaced by leucine, an amino acid with highly similar properties. This variant has been reported in the heterozygous state in two relatives with vesicoureteral reflux (Elahi S et al. Pediatr Nephrol, 2016 Feb;31:247-53). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at