5-112707523-A-C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4
The NM_001407446.1(APC):c.-195A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_001407446.1 5_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
APC | NM_001407446.1 | c.-195A>C | 5_prime_UTR_variant | Exon 1 of 16 | NP_001394375.1 | |||
APC | NM_001407447.1 | c.-378A>C | 5_prime_UTR_variant | Exon 1 of 17 | NP_001394376.1 | |||
APC | NM_001407448.1 | c.-145A>C | 5_prime_UTR_variant | Exon 1 of 17 | NP_001394377.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APC | ENST00000509732 | c.-145A>C | 5_prime_UTR_variant | Exon 1 of 16 | 4 | ENSP00000426541.2 | ||||
APC | ENST00000507379 | c.-195A>C | 5_prime_UTR_variant | Exon 1 of 14 | 2 | ENSP00000423224.2 | ||||
APC | ENST00000505350.2 | n.-195A>C | non_coding_transcript_exon_variant | Exon 1 of 16 | 3 | ENSP00000481752.1 | ||||
APC | ENST00000505350.2 | n.-195A>C | 5_prime_UTR_variant | Exon 1 of 16 | 3 | ENSP00000481752.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 5
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.-195A>C pathogenic mutation is located in the 5' untranslated region (5’ UTR) of the APC gene. This mutation results from an A to C substitution 195 bases upstream from the first translated codon. This alteration has been described in a large family with clinical gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) and completely segregated with disease in all 27 affected family members tested (Li J et al. Am. J. Hum. Genet. 2016 May;98:830-42). The alteration impacts a highly-conserved nucleotide within the YY1 binding motif of APC promoter 1B, and authors demonstrated disrupted protein binding associated with c.-195A>C. Furthermore, luciferase assay results showed significantly reduced promoter activity for this variant compared to wild type and APC allelic imbalance was observed in blood and GI tissue from affected individuals, supporting reduced in vivo expression from this allele. 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