rs1239946140
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1PP3BS2
The NM_001407446.1(APC):c.165+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000877 in 1,368,268 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000066 ( 0 hom. )
Consequence
APC
NM_001407446.1 splice_donor
NM_001407446.1 splice_donor
Scores
3
2
2
Splicing: ADA: 0.9885
2
Clinical Significance
Conservation
PhyloP100: 3.26
Genes affected
APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
BS2
?
High AC in GnomAdExome at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_001127511.3 | c.165+1G>A | splice_donor_variant | ||||
APC | NM_001354895.2 | c.-19+1G>A | splice_donor_variant | ||||
APC | NM_001354897.2 | c.165+1G>A | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000507379.6 | c.165+1G>A | splice_donor_variant | 2 | |||||
APC | ENST00000509732.6 | c.-19+234G>A | intron_variant | 4 | P1 | ||||
APC | ENST00000505350.2 | c.165+1G>A | splice_donor_variant, NMD_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152064Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000525 AC: 7AN: 133320Hom.: 0 AF XY: 0.0000689 AC XY: 5AN XY: 72558
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GnomAD4 exome AF: 0.00000658 AC: 8AN: 1216204Hom.: 0 Cov.: 31 AF XY: 0.0000101 AC XY: 6AN XY: 594044
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152064Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74288
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This variant occurs in a non-coding region of the APC gene. It does not change the encoded amino acid sequence of the APC protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 537591). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 15, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Benign
D
MutationTaster
Benign
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
Find out detailed SpliceAI scores and Pangolin per-transcript scores at