rs1060503259
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.1742delA(p.Lys581fs) variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K581K) has been classified as Likely pathogenic. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000038.6 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.1742delA | p.Lys581fs | frameshift_variant, splice_region_variant | 14/16 | ENST00000257430.9 | NP_000029.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.1742delA | p.Lys581fs | frameshift_variant, splice_region_variant | 14/16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
ENSG00000258864 | ENST00000520401.1 | n.227delA | splice_region_variant, non_coding_transcript_exon_variant | 3/8 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 27, 2016 | For these reasons, this variant has been classified as Pathogenic. Truncating variants in APC are known to be pathogenic. This particular truncation has been reported in the literature in individuals affected with familial adenomatous polyposis (FAP) (PMID: 20223039, 20685668). This sequence change deletes 1 nucleotide from exon 14 of the APC mRNA (c.1742delA), causing a frameshift at codon 581. This creates a premature translational stop signal (p.Lys581Argfs*9) and is expected to result in an absent or disrupted protein product. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 02, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Sep 13, 2022 | A heterozygous 1 base pair deletion in exon 14 of the APC gene that results in a frameshift and premature truncation of the protein 9 amino acids downstream to codon 581 was detected. The observed variant has not been reported in the 1000 genomes, gnomAD and our internal database. The in silico predictions of the variant is damaging by MutationTaster2. The reference base is conserved across species. In summary, the variant meets our criteria to be classified as a pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at