rs1484876251
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_001048174.2(MUTYH):c.1501del(p.Leu501TrpfsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L501L) has been classified as Likely benign.
Frequency
Consequence
NM_001048174.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUTYH | NM_001128425.2 | c.1585del | p.Leu529TrpfsTer42 | frameshift_variant | 16/16 | ENST00000710952.2 | |
MUTYH | NM_001048174.2 | c.1501del | p.Leu501TrpfsTer42 | frameshift_variant | 16/16 | ENST00000456914.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000710952.2 | c.1585del | p.Leu529TrpfsTer42 | frameshift_variant | 16/16 | NM_001128425.2 | |||
MUTYH | ENST00000456914.7 | c.1501del | p.Leu501TrpfsTer42 | frameshift_variant | 16/16 | 1 | NM_001048174.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74370
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 19, 2017 | The c.1585delC variant, located in coding exon 16 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 1585, causing a translational frameshift with a predicted alternate stop codon (p.L529Wfs*42). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of MUTYH, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 20 amino acids of the protein in addition to elongating the protein by 21 amino acids. The exact functional impact of these altered amino acids is unknown at this time. However, structural analysis suggests that this alteration is expected to result in loss of predicted and confirmed interaction and regulatory domains, including PCNA-binding Pip domain, which results in loss of DNA repair function in-vitro (Chang DY et al. J. Biol. Chem. 2002 Apr;277(14):11853-8), as well as gain of putative interaction motifs, including a nuclear-hormone-receptor coactivator motif (NRBOX) (Leo C et al. Gene 2000 Mar;245(1):1-11). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at