rs3219466

Positions:

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

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• 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]

ACMG classification

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. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 59 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.-127C>T		5_prime_UTR_variant	1/16	ENST00000710952.2
TOE1	NM_025077.4	c.52+77G>A		intron_variant		ENST00000372090.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.-127C>T		5_prime_UTR_variant	1/16		NM_001128425.2
TOE1	ENST00000372090.6	c.52+77G>A		intron_variant		1	NM_025077.4	P1

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

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

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:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 10, 2013	There is insufficient or conflicting evidence for classification of this alteration. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 11, 2021	- -

Familial adenomatous polyposis 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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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

Other links and lift over

dbSNP: rs3219466; hg19: chr1-45806053;