chr6-73610399-C-T
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_012434.5(SLC17A5):c.1259+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,630 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 Likely pathogenic (★★).
Frequency
Consequence
NM_012434.5 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC17A5 | NM_012434.5 | c.1259+1G>A | splice_donor_variant | ENST00000355773.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC17A5 | ENST00000355773.6 | c.1259+1G>A | splice_donor_variant | 1 | NM_012434.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251382Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135890
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461630Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727120
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Salla disease Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 07, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 02, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change affects a donor splice site in intron 9 of the SLC17A5 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs146095590, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with free sialic acid storage disorders (PMID: 12794688, 15805149). This variant is also known as IVS9+1G>A. ClinVar contains an entry for this variant (Variation ID: 370393). Studies have shown that disruption of this splice site results in skipping of exon 9 and introduces a premature termination codon (PMID: 12794688). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 23, 2020 | Variant summary: SLC17A5 c.1259+1G>A 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: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251382 control chromosomes. c.1259+1G>A has been reported in the literature in individuals affected with Sialic Acid Storage Disorder (example, Kleta_2003, Froissart_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Sialic acid storage disease, severe infantile type Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2003 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 31, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at