rs3219463

Variant names:

• chr1-45340760-C-T
• rs3219463
• NM_025077.4:c.53-313C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_025077.4(TOE1):​c.53-313C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 151,990 control chromosomes in the GnomAD database, including 5,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.27 (5839 hom., cov: 31)
• Consequence: TOE1 NM_025077.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.367
• Publications: 14 publications found

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]

ENSG00000288208 (HGNC:):

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 Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Orphanet, G2P
• colorectal cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AR, AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-45340760-C-T is Benign according to our data. Variant chr1-45340760-C-T is described in ClinVar as Benign. ClinVar VariationId is 1221523.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025077.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOE1	NM_025077.4	MANE Select	c.53-313C>T		intron	N/A	NP_079353.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOE1	ENST00000372090.6	TSL:1 MANE Select	c.53-313C>T		intron	N/A	ENSP00000361162.5	Q96GM8-1
	ENSG00000288208	ENST00000671898.1		n.541-6249G>A		intron	N/A	ENSP00000499896.1	A0A5F9ZGZ0
	TOE1	ENST00000874144.1		c.71-313C>T		intron	N/A	ENSP00000544203.1

Frequencies

GnomAD3 genomes AF: 0.270 AC: 40947 AN: 151872 Hom.: 5808 Cov.: 31

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.296

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.270 AC: 41025 AN: 151990 Hom.: 5839 Cov.: 31 AF XY: 0.269 AC XY: 20002 AN XY: 74290

African (AFR) AF: 0.275 AC: 11374 AN: 41424

American (AMR) AF: 0.403 AC: 6146 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 877 AN: 3470

East Asian (EAS) AF: 0.365 AC: 1885 AN: 5166

South Asian (SAS) AF: 0.230 AC: 1110 AN: 4816

European-Finnish (FIN) AF: 0.208 AC: 2203 AN: 10570

Middle Eastern (MID) AF: 0.271 AC: 79 AN: 292

European-Non Finnish (NFE) AF: 0.242 AC: 16468 AN: 67966

Other (OTH) AF: 0.302 AC: 637 AN: 2110

Alfa AF: 0.253 Hom.: 826

Bravo AF: 0.288

Asia WGS AF: 0.344 AC: 1194 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.6
DANN	Benign	0.68
PhyloP100		0.37
PromoterAI		-0.023	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs3219463; hg19: chr1-45806432;