1-45339894-G-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001048174.2(MUTYH):​c.-7+5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.988 in 1,401,720 control chromosomes in the GnomAD database, including 683,553 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74671 hom., cov: 31)
  • Exomes 𝑓: 0.99 (608882 hom.)
• Consequence: MUTYH NM_001048174.2 splice_region, intron
• Scores: Splicing: ADA: 0.00004900
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.00

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-45339894-G-C is Benign according to our data. Variant chr1-45339894-G-C is described in ClinVar as [Benign]. Clinvar id is 1244445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45339894-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.990 AC: 150678 AN: 152156 Hom.: 74611 Cov.: 31

Gnomad AFR AF: 0.997

Gnomad AMI AF: 0.987

Gnomad AMR AF: 0.988

Gnomad ASJ AF: 0.994

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.997

Gnomad FIN AF: 0.994

Gnomad MID AF: 0.991

Gnomad NFE AF: 0.985

Gnomad OTH AF: 0.989

GnomAD3 exomes AF: 0.990 AC: 168681 AN: 170428 Hom.: 83479 AF XY: 0.990 AC XY: 91806 AN XY: 92742

Gnomad AFR exome AF: 0.997

Gnomad AMR exome AF: 0.991

Gnomad ASJ exome AF: 0.994

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.996

Gnomad FIN exome AF: 0.991

Gnomad NFE exome AF: 0.984

Gnomad OTH exome AF: 0.986

GnomAD4 exome AF: 0.987 AC: 1233495 AN: 1249446 Hom.: 608882 Cov.: 75 AF XY: 0.987 AC XY: 606722 AN XY: 614462

Gnomad4 AFR exome AF: 0.998

Gnomad4 AMR exome AF: 0.991

Gnomad4 ASJ exome AF: 0.995

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.996

Gnomad4 FIN exome AF: 0.991

Gnomad4 NFE exome AF: 0.985

Gnomad4 OTH exome AF: 0.989

GnomAD4 genome AF: 0.990 AC: 150797 AN: 152274 Hom.: 74671 Cov.: 31 AF XY: 0.991 AC XY: 73822 AN XY: 74464

Gnomad4 AFR AF: 0.997

Gnomad4 AMR AF: 0.988

Gnomad4 ASJ AF: 0.994

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.997

Gnomad4 FIN AF: 0.994

Gnomad4 NFE AF: 0.985

Gnomad4 OTH AF: 0.989

Alfa AF: 0.985 Hom.: 7779

Bravo AF: 0.990

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Dec 21, 2021

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.25
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.10		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: rs3219468; hg19: chr1-45805566;