rs145092287
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001905.4(CTPS1):c.1692-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000564 in 1,611,348 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001905.4 splice_acceptor
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CTPS1 | NM_001905.4 | c.1692-1G>C | splice_acceptor_variant | ENST00000650070.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTPS1 | ENST00000650070.2 | c.1692-1G>C | splice_acceptor_variant | NM_001905.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000145 AC: 22AN: 152214Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000957 AC: 24AN: 250754Hom.: 0 AF XY: 0.0000885 AC XY: 12AN XY: 135566
GnomAD4 exome AF: 0.000607 AC: 886AN: 1459134Hom.: 1 Cov.: 29 AF XY: 0.000625 AC XY: 454AN XY: 726056
GnomAD4 genome ? AF: 0.000145 AC: 22AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74366
ClinVar
Submissions by phenotype
Severe combined immunodeficiency due to CTPS1 deficiency Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust | May 03, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 12, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2024 | This sequence change affects an acceptor splice site in intron 17 of the CTPS1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs145092287, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with combined immunodeficiency (PMID: 24870241, 27638562, 32161190). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 140454). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24870241). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 12, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 16, 2022 | DNA sequence analysis of the CTPS1 gene demonstrated a sequence change in the canonical splice acceptor site of intron 17, c.1692-1G>C. This sequence change is predicted to affect normal splicing of the CTPS1 gene and result in an abnormal/unstable protein. This sequence change has been previously described in the homozygous state in multiple individuals with CTPS1-related combined immunodeficiency (PMIDs: 24870241, 27638562, 32161190) and is reported to be a founder mutation in the northwest England population. Experimental studies have shown that this sequence change is responsible for reduced protein expression and may result in unstable protein lacking the last exon (PMIDs: 24870241, 32161190). This sequence change has been described in the gnomAD database with a frequency of 0.018% in the European subpopulation (dbSNP rs145092287). These collective evidences indicate that this sequence change is pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 28, 2016 | The c.1692-1G>C variant in the CTPS1 gene has been reported previously in the homozygous state inindividuals with immunodeficiency and is considered a founder mutation in the English population(Martin et al., 2014; Kucuk et al., 2016; Truck et al., 2016). This splice site variant destroys thecanonical splice acceptor site in intron 17. It is predicted to cause abnormal gene splicing, eitherleading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormalprotein product if the message is used for protein translation. The c.1692-1G>C variant was notobserved at a significant frequency in approximately 6500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. We interpret c.1692-1G>C as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 08, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at