rs761458613
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000038.6(APC):c.1743+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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_000038.6 splice_donor, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.1743+1G>A | splice_donor_variant, intron_variant | Intron 14 of 15 | 5 | NM_000038.6 | ENSP00000257430.4 | |||
ENSG00000258864 | ENST00000520401.1 | n.228+1G>A | splice_donor_variant, intron_variant | Intron 3 of 7 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1451120Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 722702
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:2
This sequence change affects a donor splice site in intron 14 of the APC 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 APC are known to be pathogenic (PMID: 17963004, 20685668). This variant is present in population databases (rs761458613, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with personal and/or family history of adenomatous polyposis (PMID: 19029688; Invitae). ClinVar contains an entry for this variant (Variation ID: 236563). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -
not provided Pathogenic:2
Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 19029688, 30720243) -
The APC c.1743+1G>A variant disrupts a canonical splice-donor site and is predicted to interfere with normal APC mRNA splicing. This variant has been reported in the published literature in an individual with familial adenomatous polyposis (FAP) (PMID: 19029688 (2008)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic. -
Classic or attenuated familial adenomatous polyposis Pathogenic:1
This variant causes a G>A nucleotide substitution at the +1 position of intron 14 of the APC gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported to impact RNA splicing (Ambry Genetics; ClinVar SCV002712125.1). This variant has been reported in individuals affected with clinical features of familial adenomatous polyposis (PMID: 19029688; ClinVar SCV002712125.1, SCV000282703.6). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice donor site, c.1743+1G>C, c.1743+1G>T, c.1743+2T>C and c.1743+2T>A, are known to be disease-causing (ClinVar variation ID: 1779228, 232800, 2447192, 1779229). Loss of APC function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. -
APC-related disorder Pathogenic:1
The APC c.1743+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in an individual with familial adenomatous polyposis coli (Table 1, Plawski et al. 2008. PubMed ID: 19029688). This variant has not been reported in a large population database, indicating it is rare. This variant has been reported in ClinVar as likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/236563/). A different splice variant at the same position (c.1743+1G>T) has also been reported in an individual with familial adenomatous polyposis coli (Table S1, Lagarde et al. 2010. PubMed ID: 20685668). Variants that disrupt consensus splice donor sites in APC are expected to be pathogenic. The c.1743+1G>A variant is interpreted as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.1743+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 13 of the APC gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay. The exact functional effect of the missing amino acids is unknown; however, many close match splice alterations that occur in individuals with FAP are known or predicted to result in the same aberrant splice event (Ambry internal data; Kaufmann A et al. J Mol Diagn, 2009 Mar;11:131-9; Lagarde A et al. J Med Genet, 2010 Oct;47:721-2). This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with APC-related disease (Ambry internal data; Plawski A et al. J Appl Genet, 2008;49:407-14). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at