rs587780742
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_001048174.2(MUTYH):c.1102+9A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,613,718 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 Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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MUTYH | ENST00000456914.7 | c.1102+9A>T | intron_variant | Intron 12 of 15 | 1 | NM_001048174.2 | ENSP00000407590.2 | |||
ENSG00000288208 | ENST00000671898.1 | n.1690+9A>T | intron_variant | Intron 16 of 20 | ENSP00000499896.1 |
Frequencies
GnomAD3 genomes AF: 0.000171 AC: 26AN: 152196Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000108 AC: 27AN: 249362Hom.: 0 AF XY: 0.000111 AC XY: 15AN XY: 135456
GnomAD4 exome AF: 0.000223 AC: 326AN: 1461404Hom.: 0 Cov.: 33 AF XY: 0.000226 AC XY: 164AN XY: 727022
GnomAD4 genome AF: 0.000171 AC: 26AN: 152314Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74476
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3
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To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00024 (12/50532 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect MUTYH mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. -
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Familial adenomatous polyposis 2 Uncertain:1Benign:3
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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
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not specified Benign:4
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Hereditary cancer-predisposing syndrome Benign:3
BP4, BP7 MUTYH c.1186+9A>T is an intronic variant not very close to a canonical splice site, where the SpliceAI algorithm predicts no significant impact on splicing (BP4 and BP7).This variant is found in 23/ 117542, with a filter allele frequency of 0.013% at 99% confidence in the gnomAD v2.1.1 database (European non-Finish non-cancer data set). In addition, the variant was identified in the ClinVar database (11x likely benign, 2, uncertain significance, 1x benign) and (2x VUS, 2x likely benign) in the LOVD database. To our knowledge, neither relevant clinical data nor functional studies have been reported for this variant. Based on currently available information, the variant c.1186+9A>T is classified as a likely benign variant according to ACMG guidelines. -
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This alteration is classified as likely benign based on a combination of the following: 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at