rs2275602

Variant names:

• chr1-45340208-G-A
• rs2275602
• NM_025077.4:c.-45G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-45340208-G-A
• chr1-45340208-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_025077.4(TOE1):​c.-45G>A variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00207 in 1,613,756 control chromosomes in the GnomAD database, including 62 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 0.0022 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (55 hom.)
• Consequence: TOE1 NM_025077.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: 4.27
• Publications: 16 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]

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

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 1-45340208-G-A is Benign according to our data. Variant chr1-45340208-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 138310.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00224 (342/152374) while in subpopulation EAS AF = 0.0313 (162/5180). AF 95% confidence interval is 0.0273. There are 7 homozygotes in GnomAd4. There are 218 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.-45G>A		5_prime_UTR	Exon 1 of 8	NP_079353.3
	MUTYH	NM_001128425.2	MANE Plus Clinical	c.36+11C>T		intron	N/A	NP_001121897.1	E5KP25
	MUTYH	NM_001407071.1		c.-12C>T		5_prime_UTR	Exon 1 of 16	NP_001394000.1	Q9UIF7-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOE1	ENST00000372090.6	TSL:1 MANE Select	c.-45G>A		5_prime_UTR	Exon 1 of 8	ENSP00000361162.5	Q96GM8-1
	MUTYH	ENST00000710952.2	MANE Plus Clinical	c.36+11C>T		intron	N/A	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000372098.7	TSL:1	c.36+11C>T		intron	N/A	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 335 AN: 152256 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0312

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00677

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00337 AC: 840 AN: 249134 AF XY: 0.00336

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0249

Gnomad FIN exome AF: 0.00866

Gnomad NFE exome AF: 0.000900

Gnomad OTH exome AF: 0.00296

GnomAD4 exome AF: 0.00206 AC: 3006 AN: 1461382 Hom.: 55 Cov.: 33 AF XY: 0.00210 AC XY: 1527 AN XY: 727016

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0397 AC: 1576 AN: 39692

South Asian (SAS) AF: 0.00266 AC: 229 AN: 86252

European-Finnish (FIN) AF: 0.00832 AC: 441 AN: 52990

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.000514 AC: 571 AN: 1111972

Other (OTH) AF: 0.00253 AC: 153 AN: 60382

GnomAD4 genome AF: 0.00224 AC: 342 AN: 152374 Hom.: 7 Cov.: 32 AF XY: 0.00293 AC XY: 218 AN XY: 74520

African (AFR) AF: 0.000192 AC: 8 AN: 41598

American (AMR) AF: 0.00105 AC: 16 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0313 AC: 162 AN: 5180

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4832

European-Finnish (FIN) AF: 0.00677 AC: 72 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68036

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.00198

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	1	2	Familial adenomatous polyposis 2 (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Carcinoma of colon (1)
-	-	1	not provided (1)
-	-	1	Pontocerebellar hypoplasia type 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.85
PhyloP100		4.3
PromoterAI		0.092	Neutral
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2275602; hg19: chr1-45805880; COSMIC: COSV59156766;