rs149342980

chr1-45332167-C-Achr1-45332167-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001048174.2(MUTYH):c.848G>T(p.Arg283Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R283K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense, splice_region
• Scores: Splicing: ADA: 0.001008
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.267

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27998066).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUTYH	NM_001128425.2	c.932G>T	p.Arg311Ile	missense_variant, splice_region_variant	10/16	ENST00000710952.2
MUTYH	NM_001048174.2	c.848G>T	p.Arg283Ile	missense_variant, splice_region_variant	10/16	ENST00000456914.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUTYH	ENST00000710952.2	c.932G>T	p.Arg311Ile	missense_variant, splice_region_variant	10/16		NM_001128425.2
MUTYH	ENST00000456914.7	c.848G>T	p.Arg283Ile	missense_variant, splice_region_variant	10/16	1	NM_001048174.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	22
Dann	Benign	0.94
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.027	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N;N;N;N;.;D
REVEL	Uncertain	0.42
Sift	Benign	0.040	D;D;D;D;D;D;D;D;D;.;D
Sift4G	Uncertain	0.013	D;D;D;D;D;D;D;D;D;D;T
Polyphen		0.024, 0.010, 0.011	.;.;.;.;.;B;B;.;B;.;.
Vest4		0.58
MutPred		0.39		.;.;.;.;.;.;.;.;Loss of disorder (P = 0.2267);.;.;
MVP		0.96
MPC		0.26
ClinPred		0.65	D
GERP RS		1.7
Varity_R		0.22
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.12
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-45797839;