1-45331472-A-T

Position:

• chr1-45331472-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001048174.2(MUTYH):​c.1187T>A​(p.Leu396Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.78

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.1271T>A	p.Leu424Gln	missense_variant	13/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.1187T>A	p.Leu396Gln	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.1271T>A	p.Leu424Gln	missense_variant	13/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.1187T>A	p.Leu396Gln	missense_variant	13/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;.;.;.;.;.;D;.;.;.;.;D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	.;.;D;.;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.6	.;.;.;.;.;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.25, 1.0	.;.;.;.;.;.;B;D;.;.;D;.
Vest4		0.78
MutPred		0.79		.;.;.;.;.;.;.;.;.;.;Gain of disorder (P = 0.0191);.;
MVP		0.96
MPC		0.56
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.66
gMVP		0.73

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: chr1-45797144;