rs863224697

Positions:

• chr1-45333456-C-A
• chr1-45333456-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001048174.2(MUTYH):​c.221G>T​(p.Ser74Ile) 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. 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. S74N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180

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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33445245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.221G>T	p.Ser74Ile	missense_variant	3/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.221G>T	p.Ser74Ile	missense_variant	3/16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.809G>T		non_coding_transcript_exon_variant	7/21			ENSP00000499896.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.29	.;.;.;.;.;T;.;.;.;T;T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.97	.;D;.;D;D;D;D;D;D;D;D;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	2.9	.;.;.;.;.;M;.;.;.;.;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.060	T;D;T;T;T;D;D;D;D;D;D;D
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;D
Polyphen		0.16, 0.85, 0.48	.;.;.;.;.;B;P;.;P;.;.;.
Vest4		0.42
MutPred		0.47		.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0334);.;.;.;
MVP		0.85
MPC		0.18
ClinPred		0.22	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr1-45799128;