rs535908547
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_006073.4(TRDN):c.1051+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000376 in 1,596,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_006073.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TRDN | NM_006073.4 | c.1051+1G>T | splice_donor_variant, intron_variant | Intron 12 of 40 | ENST00000334268.9 | NP_006064.2 | ||
TRDN | NM_001251987.2 | c.1054+1G>T | splice_donor_variant, intron_variant | Intron 12 of 20 | NP_001238916.1 | |||
TRDN | NM_001407315.1 | c.994+1G>T | splice_donor_variant, intron_variant | Intron 11 of 19 | NP_001394244.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TRDN | ENST00000334268.9 | c.1051+1G>T | splice_donor_variant, intron_variant | Intron 12 of 40 | 1 | NM_006073.4 | ENSP00000333984.5 | |||
TRDN | ENST00000662930.1 | c.1054+1G>T | splice_donor_variant, intron_variant | Intron 12 of 20 | ENSP00000499585.1 | |||||
TRDN-AS1 | ENST00000587106.6 | n.572-1541C>A | intron_variant | Intron 6 of 8 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000346 AC: 5AN: 1444048Hom.: 0 Cov.: 29 AF XY: 0.00000558 AC XY: 4AN XY: 717086
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152270Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74452
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with TRDN-related conditions. This variant is present in population databases (rs535908547, ExAC 0.01%). This sequence change affects a donor splice site in intron 12 of the TRDN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547). This variant occurs in the long isoform of TRDN, also known as Trisk-95 (PMID: 19403623). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in the long isoform of TRDN cause disease. -
Cardiovascular phenotype Uncertain:1
The c.1051+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 12 of the TRDN gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, this alteration does not impact the predominant cardiac isoform of TRDN (NM_001256021.1; Kobayashi YM et al. J. Biol. Chem., 1999 Oct;274:28660-8). 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