rs781468421
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_001044.5(SLC6A3):c.1768-7_1768-6del 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 0.0000233 in 1,590,956 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000046 ( 1 hom., cov: 33)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
SLC6A3
NM_001044.5 splice_region, splice_polypyrimidine_tract, intron
NM_001044.5 splice_region, splice_polypyrimidine_tract, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.833
Genes affected
SLC6A3 (HGNC:11049): (solute carrier family 6 member 3) This gene encodes a dopamine transporter which is a member of the sodium- and chloride-dependent neurotransmitter transporter family. The 3' UTR of this gene contains a 40 bp tandem repeat, referred to as a variable number tandem repeat or VNTR, which can be present in 3 to 11 copies. Variation in the number of repeats is associated with idiopathic epilepsy, attention-deficit hyperactivity disorder, dependence on alcohol and cocaine, susceptibility to Parkinson disease and protection against nicotine dependence.[provided by RefSeq, Nov 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000046 (7/152288) while in subpopulation EAS AF= 0.00136 (7/5162). AF 95% confidence interval is 0.000636. There are 1 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC6A3 | NM_001044.5 | c.1768-7_1768-6del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000270349.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC6A3 | ENST00000270349.12 | c.1768-7_1768-6del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_001044.5 | P1 | |||
SLC6A3 | ENST00000512002.2 | n.149-7_149-6del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152170Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.0000798 AC: 17AN: 212956Hom.: 0 AF XY: 0.0000785 AC XY: 9AN XY: 114668
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GnomAD4 exome AF: 0.0000209 AC: 30AN: 1438668Hom.: 0 AF XY: 0.0000154 AC XY: 11AN XY: 713504
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152288Hom.: 1 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74468
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Parkinsonism-dystonia, infantile Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 20, 2022 | This sequence change falls in intron 13 of the SLC6A3 gene. It does not directly change the encoded amino acid sequence of the SLC6A3 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs781468421, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with SLC6A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 538068). 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
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at