rs3219468

Variant names:

• chr1-45339894-G-A
• rs3219468
• NM_001048174.2:c.-7+5C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-45339894-G-A
• chr1-45339894-G-C
• chr1-45339894-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001048174.2(MUTYH):​c.-7+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 152,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUTYH NM_001048174.2 splice_region, intron
• Scores: Splicing: ADA: 0.00004522
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00
• Publications: 16 publications found

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]

ENSG00000288208 (HGNC:):

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)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.-7+5C>T		splice_region_variant, intron_variant	Intron 1 of 15	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.-7+5C>T		splice_region_variant, intron_variant	Intron 1 of 15	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.541-5383C>T		intron_variant	Intron 5 of 20			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000399 AC: 68 AN: 170428 AF XY: 0.000291

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000375

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00345

Gnomad NFE exome AF: 0.0000864

Gnomad OTH exome AF: 0.000421

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000183 AC: 229 AN: 1249500 Hom.: 2 Cov.: 75 AF XY: 0.000181 AC XY: 111 AN XY: 614496

African (AFR) AF: 0.0000360 AC: 1 AN: 27766

American (AMR) AF: 0.0000309 AC: 1 AN: 32330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20080

East Asian (EAS) AF: 0.00 AC: 0 AN: 22310

South Asian (SAS) AF: 0.00 AC: 0 AN: 77868

European-Finnish (FIN) AF: 0.00283 AC: 91 AN: 32212

Middle Eastern (MID) AF: 0.000206 AC: 1 AN: 4866

European-Non Finnish (NFE) AF: 0.000128 AC: 126 AN: 983602

Other (OTH) AF: 0.000186 AC: 9 AN: 48466

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152276 Hom.: 0 Cov.: 31 AF XY: 0.000228 AC XY: 17 AN XY: 74464

African (AFR) AF: 0.0000481 AC: 2 AN: 41560

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000624 Hom.: 7779

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.42
DANN	Benign	0.95
PhyloP100		-2.0
PromoterAI		0.0091	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000045
dbscSNV1_RF	Benign	0.12
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: rs3219468; hg19: chr1-45805566;