rs139977567
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting
The ENST00000456914.7(MUTYH):c.264+11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,614,156 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00066 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00052 ( 11 hom. )
Consequence
MUTYH
ENST00000456914.7 intron
ENST00000456914.7 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.33
Genes affected
MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -17 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 1-45333402-C-T is Benign according to our data. Variant chr1-45333402-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 138309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45333402-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000663 (101/152334) while in subpopulation EAS AF= 0.0189 (98/5182). AF 95% confidence interval is 0.0159. There are 1 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 11 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MUTYH | NM_001048174.2 | c.264+11G>A | intron_variant | ENST00000456914.7 | NP_001041639.1 | |||
MUTYH | NM_001128425.2 | c.348+11G>A | intron_variant | ENST00000710952.2 | NP_001121897.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000456914.7 | c.264+11G>A | intron_variant | 1 | NM_001048174.2 | ENSP00000407590 | A1 | |||
MUTYH | ENST00000710952.2 | c.348+11G>A | intron_variant | NM_001128425.2 | ENSP00000518552 |
Frequencies
GnomAD3 genomes AF: 0.000677 AC: 103AN: 152218Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00171 AC: 430AN: 251454Hom.: 9 AF XY: 0.00164 AC XY: 223AN XY: 135900
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GnomAD4 exome AF: 0.000515 AC: 753AN: 1461822Hom.: 11 Cov.: 35 AF XY: 0.000494 AC XY: 359AN XY: 727220
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GnomAD4 genome AF: 0.000663 AC: 101AN: 152334Hom.: 1 Cov.: 32 AF XY: 0.000779 AC XY: 58AN XY: 74498
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 14, 2014 | 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. - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 10, 2017 | - - |
Familial adenomatous polyposis 2 Benign:2
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Carcinoma of colon Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MUTYH c.348+11G>A variant was identified in 1 of 110 proband chromosomes (frequency: 0.001) from individuals or families with lung cancer (Shinmura 2001). The variant was also identified in dbSNP (ID: rs139977567) as With Uncertain significance allele, ClinVar (classified as benign by GeneDx; classified as uncertain significance by Illumina), Clinvitae, Insight Colon Cancer Gene Variant Database, databases. The variant was not identified in UMD-LSDB database. The variant was identified in control databases in 445 (8 homozygous) of 277170 chromosomes at a frequency of 0.0016 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 03, 2016 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at