rs3219490

Positions:

• chr1-45331583-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

The NM_001048174.2(MUTYH):​c.1103-27C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,613,578 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (17 hom.)
• Consequence: MUTYH NM_001048174.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.676

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-45331583-G-A is Benign according to our data. Variant chr1-45331583-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 801475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45331583-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome4 at 17 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001048174.2	c.1103-27C>T		intron_variant		ENST00000456914.7
MUTYH	NM_001128425.2	c.1187-27C>T		intron_variant		ENST00000710952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000456914.7	c.1103-27C>T		intron_variant		1	NM_001048174.2	A1
MUTYH	ENST00000710952.2	c.1187-27C>T		intron_variant			NM_001128425.2

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 456 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00492

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00365 AC: 908 AN: 248612 Hom.: 2 AF XY: 0.00380 AC XY: 513 AN XY: 134922

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00379

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00232

Gnomad FIN exome AF: 0.000525

Gnomad NFE exome AF: 0.00577

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.00438 AC: 6406 AN: 1461218 Hom.: 17 Cov.: 33 AF XY: 0.00443 AC XY: 3222 AN XY: 726876

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.00363

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00242

Gnomad4 FIN exome AF: 0.000455

Gnomad4 NFE exome AF: 0.00506

Gnomad4 OTH exome AF: 0.00439

GnomAD4 genome AF: 0.00299 AC: 456 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.00281 AC XY: 209 AN XY: 74506

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00492

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00447 Hom.: 0

Bravo AF: 0.00320

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2019	This variant is associated with the following publications: (PMID: 17949294, 15943555, 17524638, 16774938, 16616356, 16557584, 22297469, 20191381, 21777424, 27829682) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	MUTYH: BS1, BS2 -

Familial adenomatous polyposis 2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 05, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

MUTYH-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 02, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Jul 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.5
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs3219490; hg19: chr1-45797255; COSMIC: COSV104641844; COSMIC: COSV104641844;