NM_001003841.3:c.1173+2T>C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001003841.3(SLC6A19):c.1173+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000434 in 1,612,408 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 Likely pathogenic (★★).
Frequency
Consequence
NM_001003841.3 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC6A19 | ENST00000304460.11 | c.1173+2T>C | splice_donor_variant, intron_variant | Intron 8 of 11 | 1 | NM_001003841.3 | ENSP00000305302.10 | |||
SLC6A19 | ENST00000515652.5 | n.*118+2T>C | splice_donor_variant, intron_variant | Intron 7 of 10 | 2 | ENSP00000425701.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152220Hom.: 0 Cov.: 35
GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249668Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135256
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460188Hom.: 0 Cov.: 36 AF XY: 0.00000413 AC XY: 3AN XY: 726400
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152220Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1AN XY: 74366
ClinVar
Submissions by phenotype
Neutral 1 amino acid transport defect Pathogenic:1
Variant summary: SLC6A19 c.1173+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant creates a cryptic 5' donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 249668 control chromosomes. To our knowledge, no occurrence of c.1173+2T>C in individuals affected with Hartnup Disease and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
not provided Pathogenic:1
This sequence change affects a donor splice site in intron 8 of the SLC6A19 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), and loss-of-function variants in SLC6A19 are known to be pathogenic (PMID: 15286787, 15286788). This variant is present in population databases (rs142979576, gnomAD 0.008%). Disruption of this splice site has been observed in individuals with Hartnup disorder (PMID: 15286787, 15286788). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at