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GeneBe

rs3219466

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000372098.7(MUTYH):c.-127C>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 0.0307 in 1,553,774 control chromosomes in the GnomAD database, including 862 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 0.022 ( 59 hom., cov: 32)
Exomes 𝑓: 0.032 ( 803 hom. )

Consequence

MUTYH
ENST00000372098.7 5_prime_UTR

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.442
Variant links:
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.74).
BP6
Variant 1-45340381-G-A is Benign according to our data. Variant chr1-45340381-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428279.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chr1-45340381-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0215 (3278/152344) while in subpopulation NFE AF= 0.0342 (2324/68034). AF 95% confidence interval is 0.033. There are 59 homozygotes in gnomad4. There are 1539 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
High Homozygotes in GnomAd at 59 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MUTYHNM_001128425.2 linkuse as main transcriptc.-127C>T 5_prime_UTR_variant 1/16 ENST00000710952.2
TOE1NM_025077.4 linkuse as main transcriptc.52+77G>A intron_variant ENST00000372090.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MUTYHENST00000710952.2 linkuse as main transcriptc.-127C>T 5_prime_UTR_variant 1/16 NM_001128425.2
TOE1ENST00000372090.6 linkuse as main transcriptc.52+77G>A intron_variant 1 NM_025077.4 P1Q96GM8-1

Frequencies

GnomAD3 genomes
AF:
0.0215
AC:
3279
AN:
152226
Hom.:
59
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00591
Gnomad AMI
AF:
0.0132
Gnomad AMR
AF:
0.0153
Gnomad ASJ
AF:
0.0210
Gnomad EAS
AF:
0.000384
Gnomad SAS
AF:
0.0178
Gnomad FIN
AF:
0.0233
Gnomad MID
AF:
0.0222
Gnomad NFE
AF:
0.0342
Gnomad OTH
AF:
0.0234
GnomAD4 exome
AF:
0.0317
AC:
44373
AN:
1401430
Hom.:
803
Cov.:
33
AF XY:
0.0316
AC XY:
21841
AN XY:
691954
show subpopulations
Gnomad4 AFR exome
AF:
0.00508
Gnomad4 AMR exome
AF:
0.0114
Gnomad4 ASJ exome
AF:
0.0272
Gnomad4 EAS exome
AF:
0.0000557
Gnomad4 SAS exome
AF:
0.0195
Gnomad4 FIN exome
AF:
0.0251
Gnomad4 NFE exome
AF:
0.0356
Gnomad4 OTH exome
AF:
0.0291
GnomAD4 genome
AF:
0.0215
AC:
3278
AN:
152344
Hom.:
59
Cov.:
32
AF XY:
0.0207
AC XY:
1539
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.00589
Gnomad4 AMR
AF:
0.0153
Gnomad4 ASJ
AF:
0.0210
Gnomad4 EAS
AF:
0.000385
Gnomad4 SAS
AF:
0.0176
Gnomad4 FIN
AF:
0.0233
Gnomad4 NFE
AF:
0.0342
Gnomad4 OTH
AF:
0.0232
Alfa
AF:
0.0323
Hom.:
30
Bravo
AF:
0.0207
Asia WGS
AF:
0.00693
AC:
24
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 10, 2013There is insufficient or conflicting evidence for classification of this alteration. -
Likely benign, criteria provided, single submittercurationSema4, Sema4May 11, 2021- -
Familial adenomatous polyposis 2 Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitterclinical testingInvitaeNov 27, 2023- -
not provided Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.74
Cadd
Benign
9.4
Dann
Benign
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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: rs3219466; hg19: chr1-45806053; API