chr1-45332309-C-A

Position:

• chr1-45332309-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The ENST00000456914.7(MUTYH):​c.706G>T​(p.Gly236Cys) 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. 17/23 in silico tools predict 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. G236S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH ENST00000456914.7 missense, splice_region
• Scores: Splicing: ADA: 0.00001325
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.573

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in ENST00000456914.7
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25833976).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.790G>T	p.Gly264Cys	missense_variant, splice_region_variant	10/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.706G>T	p.Gly236Cys	missense_variant, splice_region_variant	10/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.790G>T	p.Gly264Cys	missense_variant, splice_region_variant	10/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.706G>T	p.Gly236Cys	missense_variant, splice_region_variant	10/16	1	NM_001048174.2	ENSP00000407590	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	0.090
BayesDel_addAF	Benign	0.0060	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.24	.;.;.;.;.;T;.;.;.;T;.;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.83	.;T;.;T;T;T;T;T;T;T;T;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.90	.;.;.;.;.;L;.;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N;N;N;.;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.023	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		0.044, 0.56, 0.62	.;.;.;.;.;B;P;.;P;.;.;.
Vest4		0.31
MutPred		0.50		.;.;.;.;.;.;.;.;Gain of catalytic residue at G264 (P = 0.0219);.;.;.;
MVP		0.77
MPC		0.31
ClinPred		0.47	T
GERP RS		0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0040
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: chr1-45797981;