1-45332883-T-C

Variant names:

• chr1-45332883-T-C
• rs3219487
• NM_001128425.2:c.504+35A>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.504+35A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.916 in 1,614,088 control chromosomes in the GnomAD database, including 677,042 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66325 hom., cov: 31)
  • Exomes 𝑓: 0.91 (610717 hom.)
• Consequence: MUTYH NM_001128425.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.26
• Publications: 45 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=-0.88).
• BP6: Variant 1-45332883-T-C is Benign according to our data. Variant chr1-45332883-T-C is described in ClinVar as Benign. ClinVar VariationId is 257529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.504+35A>G		intron_variant	Intron 6 of 15	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.420+35A>G		intron_variant	Intron 6 of 15	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.504+35A>G		intron_variant	Intron 6 of 15		NM_001128425.2	ENSP00000518552.2
MUTYH	ENST00000456914.7	c.420+35A>G		intron_variant	Intron 6 of 15	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1008+35A>G		intron_variant	Intron 10 of 20			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.933 AC: 141872 AN: 152118 Hom.: 66268 Cov.: 31

Gnomad AFR AF: 0.966

Gnomad AMI AF: 0.893

Gnomad AMR AF: 0.932

Gnomad ASJ AF: 0.893

Gnomad EAS AF: 0.901

Gnomad SAS AF: 0.928

Gnomad FIN AF: 0.977

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.912

Gnomad OTH AF: 0.919

GnomAD2 exomes AF: 0.926 AC: 232563 AN: 251096 AF XY: 0.924

Gnomad AFR exome AF: 0.968

Gnomad AMR exome AF: 0.953

Gnomad ASJ exome AF: 0.891

Gnomad EAS exome AF: 0.890

Gnomad FIN exome AF: 0.978

Gnomad NFE exome AF: 0.913

Gnomad OTH exome AF: 0.921

GnomAD4 exome AF: 0.914 AC: 1335987 AN: 1461852 Hom.: 610717 Cov.: 61 AF XY: 0.914 AC XY: 664326 AN XY: 727224

African (AFR) AF: 0.969 AC: 32433 AN: 33480

American (AMR) AF: 0.949 AC: 42464 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.899 AC: 23487 AN: 26136

East Asian (EAS) AF: 0.883 AC: 35052 AN: 39700

South Asian (SAS) AF: 0.918 AC: 79175 AN: 86258

European-Finnish (FIN) AF: 0.975 AC: 52059 AN: 53416

Middle Eastern (MID) AF: 0.919 AC: 5299 AN: 5768

European-Non Finnish (NFE) AF: 0.909 AC: 1010485 AN: 1111976

Other (OTH) AF: 0.920 AC: 55533 AN: 60394

GnomAD4 genome AF: 0.933 AC: 141987 AN: 152236 Hom.: 66325 Cov.: 31 AF XY: 0.936 AC XY: 69686 AN XY: 74420

African (AFR) AF: 0.966 AC: 40128 AN: 41546

American (AMR) AF: 0.932 AC: 14261 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.893 AC: 3099 AN: 3470

East Asian (EAS) AF: 0.900 AC: 4658 AN: 5176

South Asian (SAS) AF: 0.928 AC: 4470 AN: 4818

European-Finnish (FIN) AF: 0.977 AC: 10374 AN: 10616

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

European-Non Finnish (NFE) AF: 0.911 AC: 61979 AN: 67998

Other (OTH) AF: 0.920 AC: 1942 AN: 2112

Alfa AF: 0.919 Hom.: 125881

Bravo AF: 0.930

Asia WGS AF: 0.925 AC: 3217 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

- -

Apr 10, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.61
DANN	Benign	0.41
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=4/96	disease causing

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: rs3219487; hg19: chr1-45798555; COSMIC: COSV58343750; COSMIC: COSV58343750;