rs768222428

Variant names:

• chr1-45331196-T-A
• rs768222428
• NM_001048174.2:c.1378A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-45331196-T-A
• chr1-45331196-T-C
• chr1-45331196-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001048174.2(MUTYH):​c.1378A>T​(p.Thr460Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T460A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.67
• Publications: 0 publications found

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]

MUTYH Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
• colorectal cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.1378A>T	p.Thr460Ser	missense_variant	Exon 14 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.1378A>T	p.Thr460Ser	missense_variant	Exon 14 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1966A>T		non_coding_transcript_exon_variant	Exon 18 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	0.28
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.37	.;.;.;.;.;.;T;.;.;.;.;T
Eigen	Benign	-0.015
Eigen_PC	Benign	0.098
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;.;D;.;D;D;D;D;D;T;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.6	.;.;.;.;.;.;M;.;.;.;.;.
PhyloP100		5.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.5	D;N;N;N;N;N;N;N;N;D;N;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.0070	D;T;T;T;T;T;T;T;T;D;T;.
Sift4G	Pathogenic	0.0	D;T;T;T;T;T;T;T;T;D;T;T
Polyphen		0.0040, 0.037, 0.0030	.;.;.;.;.;.;B;B;.;.;B;.
Vest4		0.66
MutPred		0.33		.;.;.;.;.;.;.;.;.;.;Gain of disorder (P = 0.0994);.;
MVP		0.94
MPC		0.15
ClinPred		0.78	D
GERP RS		5.7
Varity_R		0.34
gMVP		0.34
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs768222428; hg19: chr1-45796868;