chr12-63808778-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_014254.3(RXYLT1):c.1018C>T(p.Arg340Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,132 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R340R) has been classified as Likely benign.
Frequency
Consequence
NM_014254.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RXYLT1 | NM_014254.3 | c.1018C>T | p.Arg340Ter | stop_gained | 6/6 | ENST00000261234.11 | |
RXYLT1 | NM_001278237.2 | c.238C>T | p.Arg80Ter | stop_gained | 6/6 | ||
RXYLT1 | XM_047428078.1 | c.709C>T | p.Arg237Ter | stop_gained | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RXYLT1 | ENST00000261234.11 | c.1018C>T | p.Arg340Ter | stop_gained | 6/6 | 1 | NM_014254.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152084Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250060Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135140
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461048Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 726784
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74292
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change creates a premature translational stop signal (p.Arg340*) in the RXYLT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 104 amino acid(s) of the RXYLT1 protein. This variant is present in population databases (rs397514695, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Walker-Warburg syndrome (PMID: 23519211). ClinVar contains an entry for this variant (Variation ID: 50606). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects RXYLT1 function (PMID: 23519211). This variant disrupts a region of the RXYLT1 protein in which other variant(s) (p.Asp355Valfs*33) have been determined to be pathogenic (PMID: 23217329). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 26, 2013 | - - |
Walker-Warburg congenital muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 06, 2015 | The p.Arg340X variant in TMEM5 has been reported in homozygosity in 1 individual with clinical features of Walker-Warburg syndrome (Jae 2013). This variant has been identified in 2/66,736 (~0%) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397514695). This nonsense variant leads to a premature termination codon at position 340. This alteration occurs within the last exon and is most likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In vitro functional studies provide some evidence that the p.Arg340X variant may impact protein function (Jae 2013). In addition, the absence of over 100 amino acids from the protein is likely to impact its stability and/or function. Homozygous or compound heterozygous loss of function of TMEM5 has been shown to cause congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies. In summary, this variant meets our criteria to be classified as pathogenic for dystroglycanopathy in an autosomal recessive manner. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at