rs201397168
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_001365276.2(TNXB):c.6074A>T(p.Asp2025Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0005 in 1,613,814 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001365276.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNXB | NM_001365276.2 | c.6074A>T | p.Asp2025Val | missense_variant | 17/44 | ENST00000644971.2 | |
TNXB | NM_019105.8 | c.6074A>T | p.Asp2025Val | missense_variant | 17/44 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNXB | ENST00000644971.2 | c.6074A>T | p.Asp2025Val | missense_variant | 17/44 | NM_001365276.2 | |||
TNXB | ENST00000647633.1 | c.6815A>T | p.Asp2272Val | missense_variant | 18/45 | P1 | |||
TNXB | ENST00000375244.7 | c.6074A>T | p.Asp2025Val | missense_variant | 17/44 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000539 AC: 82AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000923 AC: 230AN: 249130Hom.: 1 AF XY: 0.000880 AC XY: 119AN XY: 135198
GnomAD4 exome AF: 0.000496 AC: 725AN: 1461632Hom.: 7 Cov.: 33 AF XY: 0.000529 AC XY: 385AN XY: 727102
GnomAD4 genome ? AF: 0.000539 AC: 82AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.000605 AC XY: 45AN XY: 74342
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, type 3 Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NM_019105.6:c.6074A>T in the TNXB gene has an allele frequency of 0.018 in Ashkenazi Jewish subpopulation in the gnomAD database. Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, MutationTaster and SIFT. It has been detected in heterozygous state in one individual with Ehlers-Danlos syndrome (PMID: 25326637). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP3; PP4. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | UCLA Clinical Genomics Center, UCLA | Feb 05, 2013 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 22, 2021 | Reported as a single heterozygous variant in association with joint pain, hypermobility, chronic muscle weakness, and Raynaud's phenomenon (Lee et al., 2014; Kaufman et al., 2016); however no segregation data is available, and at least one patient is Ashkenazi Jewish; This variant is associated with the following publications: (PMID: 31589614, 26582918, 25326637, 28344932) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | TNXB: BP4, BS2 - |
Ehlers-Danlos syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Feb 23, 2022 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 03, 2019 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at