1-45331502-T-A

Variant names:

• chr1-45331502-T-A
• NM_001048174.2:c.1157A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_001048174.2(MUTYH):​c.1157A>T​(p.Gln386Leu) 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. 15/21 in silico tools predict 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. Q386R) has been classified as Pathogenic.

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

ENSG00000288208 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a strand (size 9) in uniprot entity MUTYH_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1662637).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.1157A>T	p.Gln386Leu	missense_variant	Exon 13 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.1157A>T	p.Gln386Leu	missense_variant	Exon 13 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1745A>T		non_coding_transcript_exon_variant	Exon 17 of 21			ENSP00000499896.1

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	Benign	0.082
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	7.8
DANN	Benign	0.88
DEOGEN2	Uncertain	0.50	.;.;.;.;.;.;D;.;.;.;.;D
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.60	.;.;T;.;T;T;T;T;T;T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	.;.;.;.;.;.;L;.;.;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Benign	0.13
Sift	Uncertain	0.011	D;T;T;T;T;T;T;T;T;D;T;.
Sift4G	Uncertain	0.049	D;T;T;T;T;T;T;T;T;D;T;T
Polyphen		0.0	.;.;.;.;.;.;B;B;.;.;B;.
Vest4		0.25
MutPred		0.45		.;.;.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0339);.;
MVP		0.88
MPC		0.11
ClinPred		0.084	T
GERP RS		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.40

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: chr1-45797174;