1-45330597-G-C

Variant names:

• chr1-45330597-G-C
• rs3219493
• NM_001128425.2:c.1477-40C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001128425.2(MUTYH):​c.1477-40C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.914 in 1,590,222 control chromosomes in the GnomAD database, including 664,951 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (65876 hom., cov: 32)
  • Exomes 𝑓: 0.91 (599075 hom.)
• Consequence: MUTYH NM_001128425.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.263
• Publications: 28 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]

MUTYH Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 2

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

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 1-45330597-G-C is Benign according to our data. Variant chr1-45330597-G-C is described in ClinVar as Benign. ClinVar VariationId is 439920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128425.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	NM_001128425.2	MANE Plus Clinical	c.1477-40C>G		intron	N/A	NP_001121897.1
	MUTYH	NM_001048174.2	MANE Select	c.1393-40C>G		intron	N/A	NP_001041639.1
	MUTYH	NM_012222.3		c.1468-40C>G		intron	N/A	NP_036354.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	ENST00000710952.2	MANE Plus Clinical	c.1477-40C>G		intron	N/A	ENSP00000518552.2
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.1393-40C>G		intron	N/A	ENSP00000407590.2
	MUTYH	ENST00000372098.7	TSL:1	c.1468-40C>G		intron	N/A	ENSP00000361170.3

Frequencies

GnomAD3 genomes AF: 0.929 AC: 141427 AN: 152158 Hom.: 65830 Cov.: 32

Gnomad AFR AF: 0.957

Gnomad AMI AF: 0.894

Gnomad AMR AF: 0.929

Gnomad ASJ AF: 0.887

Gnomad EAS AF: 0.900

Gnomad SAS AF: 0.926

Gnomad FIN AF: 0.977

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.911

Gnomad OTH AF: 0.918

GnomAD2 exomes AF: 0.925 AC: 199278 AN: 215550 AF XY: 0.922

Gnomad AFR exome AF: 0.959

Gnomad AMR exome AF: 0.951

Gnomad ASJ exome AF: 0.884

Gnomad EAS exome AF: 0.891

Gnomad FIN exome AF: 0.978

Gnomad NFE exome AF: 0.912

Gnomad OTH exome AF: 0.920

GnomAD4 exome AF: 0.913 AC: 1312359 AN: 1437946 Hom.: 599075 Cov.: 36 AF XY: 0.912 AC XY: 650648 AN XY: 713204

African (AFR) AF: 0.958 AC: 31416 AN: 32788

American (AMR) AF: 0.948 AC: 39372 AN: 41546

Ashkenazi Jewish (ASJ) AF: 0.892 AC: 22879 AN: 25636

East Asian (EAS) AF: 0.883 AC: 34000 AN: 38526

South Asian (SAS) AF: 0.916 AC: 75772 AN: 82694

European-Finnish (FIN) AF: 0.975 AC: 50693 AN: 52014

Middle Eastern (MID) AF: 0.917 AC: 5268 AN: 5742

European-Non Finnish (NFE) AF: 0.908 AC: 998420 AN: 1099524

Other (OTH) AF: 0.917 AC: 54539 AN: 59476

GnomAD4 genome AF: 0.929 AC: 141531 AN: 152276 Hom.: 65876 Cov.: 32 AF XY: 0.933 AC XY: 69491 AN XY: 74450

African (AFR) AF: 0.957 AC: 39761 AN: 41562

American (AMR) AF: 0.929 AC: 14219 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.887 AC: 3078 AN: 3472

East Asian (EAS) AF: 0.900 AC: 4654 AN: 5172

South Asian (SAS) AF: 0.926 AC: 4460 AN: 4814

European-Finnish (FIN) AF: 0.977 AC: 10380 AN: 10622

Middle Eastern (MID) AF: 0.895 AC: 263 AN: 294

European-Non Finnish (NFE) AF: 0.911 AC: 61968 AN: 68022

Other (OTH) AF: 0.919 AC: 1933 AN: 2104

Alfa AF: 0.921 Hom.: 11932

Bravo AF: 0.926

Asia WGS AF: 0.922 AC: 3207 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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

Mar 30, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial adenomatous polyposis 2 Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	7.9
DANN	Benign	0.46
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

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: rs3219493; hg19: chr1-45796269;