rs144111588

Variant names:

• chr1-45330550-C-G
• rs144111588
• NM_001048174.2:c.1400G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-45330550-C-G
• chr1-45330550-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001048174.2(MUTYH):​c.1400G>C​(p.Arg467Pro) variant causes a missense 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R467H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.15

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.1400G>C	p.Arg467Pro	missense_variant	Exon 15 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.1400G>C	p.Arg467Pro	missense_variant	Exon 15 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1988G>C		non_coding_transcript_exon_variant	Exon 19 of 21			ENSP00000499896.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

May 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MUTYH c.1484G>C (p.Arg495Pro) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 241088 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1484G>C in individuals affected with MUTYH-Associated Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 962744). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial adenomatous polyposis 2 Uncertain:1

Aug 08, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with proline at codon 495 of the MUTYH protein (p.Arg495Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Universal Mutation Database (PMID: 10612827). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.44	.;.;.;.;.;.;T;.;.;.;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.89	.;.;D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	.;.;.;.;.;.;L;.;.;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.7	D;N;N;N;N;N;N;N;N;D;N;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Benign	0.090	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0050, 0.0080, 0.0	.;.;.;.;.;.;B;B;.;.;B;.
Vest4		0.76
MutPred		0.59		.;.;.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 3e-04);.;
MVP		0.93
MPC		0.17
ClinPred		0.41	T
GERP RS		2.6
Varity_R		0.84
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144111588; hg19: chr1-45796222;