chr1-45333403-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_001048174.2(MUTYH):c.264+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001048174.2 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000456914.7 | c.264+10C>T | intron_variant | Intron 3 of 15 | 1 | NM_001048174.2 | ENSP00000407590.2 | |||
ENSG00000288208 | ENST00000671898.1 | n.852+10C>T | intron_variant | Intron 7 of 20 | ENSP00000499896.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461790Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4AN XY: 727198
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
PM2_SUP, BP4 -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.348+10C>T intronic variant results from a C to T substitution 10 nucleotides after coding exon 3 in the MUTYH gene. This variant has been reported in the homozygous state in a proband with attenuated familial adenomatous polyposis (Fokkema IF et al. Hum Mutat, 2011 May;32:557-63). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
not specified Uncertain:1
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Familial adenomatous polyposis 2 Uncertain:1
This sequence change falls in intron 3 of the MUTYH gene. It does not directly change the encoded amino acid sequence of the MUTYH protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with colorectal cancer (PMID: 35534704). ClinVar contains an entry for this variant (Variation ID: 951920). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at