rs121908383

Positions:

• chr1-45331502-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

The NM_001048174.2(MUTYH):​c.1157A>G​(p.Gln386Arg) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.103

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 4 ACMG points.

• PM1: In a strand (size 9) in uniprot entity MUTYH_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-45331502-T-C is Pathogenic according to our data. Variant chr1-45331502-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 5299.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-45331502-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.10986549). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.1241A>G	p.Gln414Arg	missense_variant	13/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.1157A>G	p.Gln386Arg	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.1241A>G	p.Gln414Arg	missense_variant	13/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.1157A>G	p.Gln386Arg	missense_variant	13/16	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: no assertion criteria provided

Submissions by phenotype

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 02, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	5.4
DANN	Benign	0.66
DEOGEN2	Benign	0.32	.;.;.;.;.;.;T;.;.;.;.;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.52	.;.;T;.;T;T;T;T;T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;.;.;.;.;.;L;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.11
Sift	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;.;.;.;B;B;.;.;B;.
Vest4		0.13
MutPred		0.33		.;.;.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0368);.;
MVP		0.89
MPC		0.12
ClinPred		0.043	T
GERP RS		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.26

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

LitVar

Other links and lift over

dbSNP: rs121908383; hg19: chr1-45797174;