5-112839326-A-G
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000038.6(APC):c.3732A>G(p.Gln1244Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,613,316 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Consequence
NM_000038.6 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -21 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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APC | ENST00000257430.9 | c.3732A>G | p.Gln1244Gln | synonymous_variant | Exon 16 of 16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
ENSG00000258864 | ENST00000520401.1 | n.228+10354A>G | intron_variant | Intron 3 of 7 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes AF: 0.0108 AC: 1651AN: 152188Hom.: 30 Cov.: 32
GnomAD3 exomes AF: 0.00304 AC: 759AN: 249614Hom.: 14 AF XY: 0.00224 AC XY: 303AN XY: 135044
GnomAD4 exome AF: 0.00103 AC: 1511AN: 1461010Hom.: 27 Cov.: 33 AF XY: 0.000922 AC XY: 670AN XY: 726742
GnomAD4 genome AF: 0.0109 AC: 1657AN: 152306Hom.: 30 Cov.: 32 AF XY: 0.0108 AC XY: 801AN XY: 74488
ClinVar
Submissions by phenotype
not specified Benign:8
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The APC p.Gln1244Gln variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant was identified in the dbSNP (ID: rs74380081) “with benign allele”, the ClinVar database (classified as “benign” by Ambry Genetics), the Clinvitae database (classified as a “variant of unknown significance by Emory Genetics), and the UMD (3X, classified as “likely neutral”). In the UMD database, the variant was identified with a co-occurring pathogenic APC variant (c.4666delA (p.Thr1556LeufsX9)), increasing the likelihood that the p.Gln1244Gln variant does not have clinical significance. In addition, the variant was identified in several populations at polymorphic allelic frequencies: 1000 Genomes Project (frequency: 0.014), the African population in the Exome Aggregation Consortium (ExAC) database (frequency: 0.038), and the African American cohort of the Exome Variant Server ESP Project (frequency: 0.036). The variant was not identified in the literature, nor was it identified in any of the following databases: InSiGHT Colon Cancer Gene Variant Database, “Zhejiang Colon Cancer Database”, GeneInsight COGR database, COSMIC. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the creation of a potential cryptic 3’ (splice donor) site; however, this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -
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Hereditary cancer-predisposing syndrome Benign:4
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This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Familial adenomatous polyposis 1 Benign:3
This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
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APC-Associated Polyposis Disorders Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at