1-45329401-G-C

Position:

• chr1-45329401-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001048174.2(MUTYH):​c.1471C>G​(p.Arg491Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. R491Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.666

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15290385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.1471C>G	p.Arg491Gly	missense_variant	16/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.1471C>G	p.Arg491Gly	missense_variant	16/16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.*214C>G		non_coding_transcript_exon_variant	21/21			ENSP00000499896.1
ENSG00000288208	ENST00000671898	n.*214C>G		3_prime_UTR_variant	15/15			ENSP00000499896.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2024

The p.R519G variant (also known as c.1555C>G), located in coding exon 16 of the MUTYH gene, results from a C to G substitution at nucleotide position 1555. The arginine at codon 519 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	.;.;.;.;.;.;T;.;.;.;.;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.83	.;.;T;.;T;T;T;T;T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.12
Sift	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.042	D;T;T;T;T;T;T;T;T;D;T;T
Polyphen		0.94, 0.99, 0.97	.;.;.;.;.;.;P;D;.;.;D;.
Vest4		0.26
MutPred		0.36		.;.;.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0093);.;
MVP		0.82
MPC		0.15
ClinPred		0.39	T
GERP RS		0.16
Varity_R		0.072
gMVP		0.28

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-45795073;