rs863224452
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_001048174.2(MUTYH):c.305-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
MUTYH
NM_001048174.2 splice_acceptor
NM_001048174.2 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.56
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 Pathogenic. Variant got 16 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.046615582 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.8, offset of 12, new splice context is: tcccccggtgtgggtctcAGagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 1-45333172-T-C is Pathogenic according to our data. Variant chr1-45333172-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 215998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45333172-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUTYH | NM_001048174.2 | c.305-2A>G | splice_acceptor_variant | ENST00000456914.7 | |||
MUTYH | NM_001128425.2 | c.389-2A>G | splice_acceptor_variant | ENST00000710952.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000456914.7 | c.305-2A>G | splice_acceptor_variant | 1 | NM_001048174.2 | A1 | |||
MUTYH | ENST00000710952.2 | c.389-2A>G | splice_acceptor_variant | NM_001128425.2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 20, 2022 | For these reasons, this variant has been classified as Pathogenic. 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: 215998). This variant is also known as c.347-2A>G. Disruption of this splice site has been observed in individuals with colorectal polyposis (PMID: 15366000, 19732775; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 of the MUTYH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 01, 2023 | The c.389-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 5 in the MUTYH gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant was identified in the homozygous state in a study that looked at the phenotypic spectrum of MUTYH-Associated Polyposis (MAP) in the context of multi-gene hereditary cancer panel testing (Sutcliffe EG et al. Fam. Cancer, 2019 04;18:203-209). Two other alterations that affect the same canonical splice acceptor site, c.389-1G>A and c.389-1G>C, have been reported as pathogenic based on being identified in conjunction with MUTYH pathogenic mutations in individuals with polyposis (Sampson JR et al. Lancet 2003 Jul;362:39-41; Vogt S et al. Gastroenterology 2009 Dec;137(6):1976-85.e1-10; Isidro G et al. Hum. Mutat. 2004 Oct;24:353-4; Torrezan GT et al. Orphanet J Rare Dis. 2013 Apr;8:54; Filipe B et al. Clin. Genet. 2009 Sep;76:242-55). 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D;D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -14
DS_AL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at