rs3219466

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000481571.5(MUTYH):n.-127C>T variant causes a non coding transcript exon 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
ENST00000481571.5 non_coding_transcript_exon

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.442

Publications

13 publications found

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]

MUTYH links:

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]

TOE1 Gene-Disease associations (from GenCC):

pontocerebellar hypoplasia type 7
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

TOE1 links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 428279.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 59 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001128425.2 link	c.-127C>T		5_prime_UTR_variant	Exon 1 of 16	ENST00000710952.2	NP_001121897.1
TOE1	NM_025077.4 link	c.52+77G>A		intron_variant	Intron 1 of 7	ENST00000372090.6	NP_079353.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
MUTYH	ENST00000710952.2 link	c.-127C>T	5_prime_UTR_variant	Exon 1 of 16		NM_001128425.2	ENSP00000518552.2
TOE1	ENST00000372090.6 link	c.52+77G>A	intron_variant	Intron 1 of 7	1	NM_025077.4	ENSP00000361162.5
ENSG00000288208	ENST00000671898.1 link	n.541-5870C>T	intron_variant	Intron 5 of 20			ENSP00000499896.1

Frequencies

GnomAD3 genomes

AF:

0.0215

AC:

3279

AN:

152226

Hom.:

Cov.:

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.:

AF XY:

0.0316

AC XY:

21841

AN XY:

691954

show subpopulations

African (AFR)

AF:

0.00508

AC:

161

AN:

31714

American (AMR)

AF:

0.0114

AC:

412

AN:

36046

Ashkenazi Jewish (ASJ)

AF:

0.0272

AC:

686

AN:

25212

East Asian (EAS)

AF:

0.0000557

AC:

AN:

35912

South Asian (SAS)

AF:

0.0195

AC:

1552

AN:

79498

European-Finnish (FIN)

AF:

0.0251

AC:

1179

AN:

47010

Middle Eastern (MID)

AF:

0.0271

AC:

154

AN:

5678

European-Non Finnish (NFE)

AF:

0.0356

AC:

38532

AN:

1082174

Other (OTH)

AF:

0.0291

AC:

1695

AN:

58186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

2769

5539

8308

11078

13847

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1446

2892

4338

5784

7230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0215

AC:

3278

AN:

152344

Hom.:

Cov.:

AF XY:

0.0207

AC XY:

1539

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00589

AC:

245

AN:

41578

American (AMR)

AF:

0.0153

AC:

234

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

AN:

3468

East Asian (EAS)

AF:

0.000385

AC:

AN:

5194

South Asian (SAS)

AF:

0.0176

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0233

AC:

247

AN:

10612

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0342

AC:

2324

AN:

68034

Other (OTH)

AF:

0.0232

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

166

331

497

662

828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0317

Hom.:

Bravo

AF:

0.0207

Asia WGS

AF:

0.00693

AC:

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

Jan 10, 2013

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

There is insufficient or conflicting evidence for classification of this alteration. -

May 11, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Familial adenomatous polyposis 2

Benign:2

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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. -

not provided

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

9.4

(source)

DANN

Benign

0.78

PhyloP100

0.44

PromoterAI

-0.030

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over