1-45331299-A-C

Position:

• chr1-45331299-A-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001048174.2(MUTYH):​c.1275T>G​(p.Tyr425Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.364

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-45331299-A-C is Pathogenic according to our data. Variant chr1-45331299-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 947743.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.1359T>G	p.Tyr453Ter	stop_gained	14/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.1275T>G	p.Tyr425Ter	stop_gained	14/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.1359T>G	p.Tyr453Ter	stop_gained	14/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.1275T>G	p.Tyr425Ter	stop_gained	14/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 19, 2019

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). This variant has not been reported in the literature in individuals with MUTYH-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr453*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Benign	-0.079
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.66	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A;D
Vest4		0.82
ClinPred		1.0	D
GERP RS		-2.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs774968843; hg19: chr1-45796971;