chr1-45340199-G-T
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_025077.4(TOE1):c.-54G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,538 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000066 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000081 ( 0 hom. )
Consequence
TOE1
NM_025077.4 5_prime_UTR
NM_025077.4 5_prime_UTR
Scores
2
Splicing: ADA: 0.00007049
2
Clinical Significance
Conservation
PhyloP100: -0.273
Genes affected
TOE1 (HGNC:15954): (target of EGR1, exonuclease) Enables poly(A)-specific ribonuclease activity and snRNA binding activity. Involved in RNA phosphodiester bond hydrolysis, exonucleolytic and snRNA 3'-end processing. Located in Cajal body and cytoplasm. Implicated in pontocerebellar hypoplasia type 7. [provided by Alliance of Genome Resources, Apr 2022]
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 -7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
Variant 1-45340199-G-T is Benign according to our data. Variant chr1-45340199-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182687.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000656 (10/152352) while in subpopulation SAS AF= 0.00207 (10/4830). AF 95% confidence interval is 0.00112. There are 1 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TOE1 | NM_025077.4 | c.-54G>T | 5_prime_UTR_variant | 1/8 | ENST00000372090.6 | ||
MUTYH | NM_001128425.2 | c.36+20C>A | intron_variant | ENST00000710952.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TOE1 | ENST00000372090.6 | c.-54G>T | 5_prime_UTR_variant | 1/8 | 1 | NM_025077.4 | P1 | ||
MUTYH | ENST00000710952.2 | c.36+20C>A | intron_variant | NM_001128425.2 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152234Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000149 AC: 37AN: 248508Hom.: 0 AF XY: 0.000222 AC XY: 30AN XY: 135058
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GnomAD4 exome AF: 0.0000814 AC: 119AN: 1461186Hom.: 0 Cov.: 33 AF XY: 0.000131 AC XY: 95AN XY: 726906
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GnomAD4 genome AF: 0.0000656 AC: 10AN: 152352Hom.: 1 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74506
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 2 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 20, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 08, 2016 | This variant is denoted MUTYH c.36+20C>A or IVS1+20C>A and consists of a C>A nucleotide substitution at the +20 position of intron 1 of the MUTYH gene. Multiple in silico models predict this variant to create a cryptic donor site in intron 1, and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MUTYH c.36+20C>A 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. The cytosine (C) nucleotide that is altered is not conserved across species. Based on currently available information, it is unclear whether MUTYH c.36+20C>A is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 03, 2016 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at