rs754735292
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000360.4(TH):c.978-3C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000356 in 1,600,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_000360.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TH | NM_000360.4 | c.978-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000352909.8 | |||
TH | NM_199292.3 | c.1071-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||
TH | NM_199293.3 | c.1059-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||
TH | XM_011520335.3 | c.990-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TH | ENST00000352909.8 | c.978-3C>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000360.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152242Hom.: 0 Cov.: 34
GnomAD4 exome AF: 0.0000359 AC: 52AN: 1448624Hom.: 0 Cov.: 32 AF XY: 0.0000333 AC XY: 24AN XY: 719836
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152242Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74374
ClinVar
Submissions by phenotype
Autosomal recessive DOPA responsive dystonia Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 11, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2022 | This sequence change falls in intron 9 of the TH gene. It does not directly change the encoded amino acid sequence of the TH protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TH-related conditions. ClinVar contains an entry for this variant (Variation ID: 583092). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at