chr1-45332466-T-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_001048174.2(MUTYH):āc.629A>Cā(p.Asn210Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N210S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001048174.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000456914.7 | c.629A>C | p.Asn210Thr | missense_variant | Exon 9 of 16 | 1 | NM_001048174.2 | ENSP00000407590.2 | ||
ENSG00000288208 | ENST00000671898.1 | n.1217A>C | non_coding_transcript_exon_variant | Exon 13 of 21 | ENSP00000499896.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461786Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 727184
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:1
This variant is denoted MUTYH c.713A>C at the cDNA level, p.Asn238Thr (N238T) at the protein level, and results in the change of an Asparagine to a Threonine (AAC>ACC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH Asn238Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Asparagine and Threonine share similar properties, this is considered a conservative amino acid substitution. MUTYH Asn238Thr occurs at a position that is conserved across species and is located in the FES cluster domain (Ruggieri 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MUTYH Asn238Thr is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Familial adenomatous polyposis 2 Uncertain:1
This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 238 of the MUTYH protein (p.Asn238Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 419292). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.N238T variant (also known as c.713A>C), located in coding exon 9 of the MUTYH gene, results from an A to C substitution at nucleotide position 713. The asparagine at codon 238 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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