1-45331433-C-G

Position:

• chr1-45331433-C-G

Variant summary

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

The NM_001048174.2(MUTYH):​c.1226G>C​(p.Arg409Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R409Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.109

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.1310G>C	p.Arg437Pro	missense_variant	13/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.1226G>C	p.Arg409Pro	missense_variant	13/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.1310G>C	p.Arg437Pro	missense_variant	13/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.1226G>C	p.Arg409Pro	missense_variant	13/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Uncertain	0.51	.;.;.;.;.;.;D;.;.;.;.;D
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.88	.;.;D;.;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.2	.;.;.;.;.;.;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.8	D;N;N;N;N;N;N;N;N;D;N;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.021	D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.036	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.0070, 0.58, 0.45	.;.;.;.;.;.;B;P;.;.;B;.
Vest4		0.45
MutPred		0.53		.;.;.;.;.;.;.;.;.;.;Gain of glycosylation at T434 (P = 0.0589);.;
MVP		0.90
MPC		0.17
ClinPred		0.67	D
GERP RS		-2.8
Varity_R		0.60
gMVP		0.82

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: chr1-45797105;