rs876658641
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001048174.2(MUTYH):c.420G>A(p.Glu140=) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001048174.2 splice_region, synonymous
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUTYH | NM_001128425.2 | c.504G>A | p.Glu168= | splice_region_variant, synonymous_variant | 6/16 | ENST00000710952.2 | |
MUTYH | NM_001048174.2 | c.420G>A | p.Glu140= | splice_region_variant, synonymous_variant | 6/16 | ENST00000456914.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000710952.2 | c.504G>A | p.Glu168= | splice_region_variant, synonymous_variant | 6/16 | NM_001128425.2 | |||
MUTYH | ENST00000456914.7 | c.420G>A | p.Glu140= | splice_region_variant, synonymous_variant | 6/16 | 1 | NM_001048174.2 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250620Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135486
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461856Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2AN XY: 727234
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 22, 2023 | The c.504G>A variant (also known as p.E168E), located in coding exon 6 of the MUTYH gene, results from a G to A substitution at nucleotide position 504. This nucleotide substitution does not change the glutamic acid at codon 168. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. This variant has been detected in conjunction with a MUTYH pathogenic variant in an individual with clinical features of MUTYH-associated polyposis (MAP); however, the phase of the two variants is unknown (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript preserves the reading frame and is not expected to trigger nonsense-mediated mRNA decay; however, the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 09, 2023 | This variant causes a G>A nucleotide substitution in the last nucleotide of exon 6 in the MUTYH gene. Splice site prediction tools suggest that this variant may impact RNA splicing, potentially disrupting the consensus donor splice site for this exon. This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar SCV000274164.6). This variant has been reported in an individual affected with early-onset colorectal cancer (PMID: 33359728). This variant has been identified in 1/250620 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Familial adenomatous polyposis 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 27, 2023 | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 230572). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change affects codon 168 of the MUTYH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MUTYH protein. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This variant causes a G>A nucleotide substitution in the last nucleotide of exon 6 in the MUTYH gene. Splice site prediction tools suggest that this variant may impact RNA splicing, potentially disrupting the consensus donor splice site for this exon. This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar SCV000274164.6). This variant has been reported in an individual affected with early-onset colorectal cancer (PMID: 33359728). This variant has been identified in 1/250620 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 09, 2020 | Variant summary: MUTYH c.504G>A (p.Glu168Glu) alters a conserved nucleotide located at the last position of exon 6 adjacent to the canonical donor splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250620 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.504G>A in individuals affected with MUTYH-Associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at