rs3219466

Variant names:

• chr1-45340381-G-A
• rs3219466
• ENST00000372098.7:c.-127C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-45340381-G-A
• chr1-45340381-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001128425.2(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 NM_001128425.2 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.442

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]

ENSG00000288208 (HGNC:):

ACMG classification

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 id is 428279.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, 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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 59 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOE1	NM_025077.4	c.52+77G>A		intron_variant	Intron 1 of 7	ENST00000372090.6	NP_079353.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOE1	ENST00000372090.6	c.52+77G>A		intron_variant	Intron 1 of 7	1	NM_025077.4	ENSP00000361162.5
ENSG00000288208	ENST00000671898.1	n.541-5870C>T		intron_variant	Intron 5 of 20			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3279 AN: 152226 Hom.: 59 Cov.: 32

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

Gnomad4 AFR exome AF: 0.00508 AC: 161 AN: 31714

Gnomad4 AMR exome AF: 0.0114 AC: 412 AN: 36046

Gnomad4 ASJ exome AF: 0.0272 AC: 686 AN: 25212

Gnomad4 EAS exome AF: 0.0000557 AC: 2 AN: 35912

Gnomad4 SAS exome AF: 0.0195 AC: 1552 AN: 79498

Gnomad4 FIN exome AF: 0.0251 AC: 1179 AN: 47010

Gnomad4 NFE exome AF: 0.0356 AC: 38532 AN: 1082174

Gnomad4 Remaining exome AF: 0.0291 AC: 1695 AN: 58186

GnomAD4 genome AF: 0.0215 AC: 3278 AN: 152344 Hom.: 59 Cov.: 32 AF XY: 0.0207 AC XY: 1539 AN XY: 74490

Gnomad4 AFR AF: 0.00589 AC: 0.00589254 AN: 0.00589254

Gnomad4 AMR AF: 0.0153 AC: 0.0152841 AN: 0.0152841

Gnomad4 ASJ AF: 0.0210 AC: 0.0210496 AN: 0.0210496

Gnomad4 EAS AF: 0.000385 AC: 0.00038506 AN: 0.00038506

Gnomad4 SAS AF: 0.0176 AC: 0.0175983 AN: 0.0175983

Gnomad4 FIN AF: 0.0233 AC: 0.0232755 AN: 0.0232755

Gnomad4 NFE AF: 0.0342 AC: 0.0341594 AN: 0.0341594

Gnomad4 OTH AF: 0.0232 AC: 0.0231788 AN: 0.0231788

Alfa AF: 0.0317 Hom.: 52

Bravo AF: 0.0207

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

May 11, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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. -

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
DANN	Benign	0.78
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs3219466; hg19: chr1-45806053;