chr1-45340199-G-T

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

Scores

2
Splicing: ADA: 0.00007049
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -0.273
Variant links:
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]

Genome browser will be placed here

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
TOE1NM_025077.4 linkuse as main transcriptc.-54G>T 5_prime_UTR_variant 1/8 ENST00000372090.6
MUTYHNM_001128425.2 linkuse as main transcriptc.36+20C>A intron_variant ENST00000710952.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TOE1ENST00000372090.6 linkuse as main transcriptc.-54G>T 5_prime_UTR_variant 1/81 NM_025077.4 P1Q96GM8-1
MUTYHENST00000710952.2 linkuse as main transcriptc.36+20C>A intron_variant NM_001128425.2

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152234
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000149
AC:
37
AN:
248508
Hom.:
0
AF XY:
0.000222
AC XY:
30
AN XY:
135058
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00111
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000893
Gnomad OTH exome
AF:
0.000330
GnomAD4 exome
AF:
0.0000814
AC:
119
AN:
1461186
Hom.:
0
Cov.:
33
AF XY:
0.000131
AC XY:
95
AN XY:
726906
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00125
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.0000656
AC:
10
AN:
152352
Hom.:
1
Cov.:
32
AF XY:
0.000107
AC XY:
8
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

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
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingCounsylApr 20, 2016- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 08, 2016This 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 submitterclinical testingColor Diagnostics, LLC DBA Color HealthMay 03, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.77
CADD
Benign
5.7
DANN
Benign
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000070
dbscSNV1_RF
Benign
0.0
SpliceAI score (max)
0.73
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.73
Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs540793556; hg19: chr1-45805871; API