rs1428261191

Variant names:

• chr1-45332777-C-T
• rs1428261191
• NM_001128425.2:c.562G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001048174.2(MUTYH):​c.478G>A​(p.Glu160Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,192 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E160V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.56
• Publications: 6 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: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet
• 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: AR, AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 52 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001048174.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	NM_001128425.2	MANE Plus Clinical	c.562G>A	p.Glu188Lys	missense	Exon 7 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.478G>A	p.Glu160Lys	missense	Exon 7 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.553G>A	p.Glu185Lys	missense	Exon 7 of 16	NP_036354.1	Q9UIF7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	ENST00000710952.2	MANE Plus Clinical	c.562G>A	p.Glu188Lys	missense	Exon 7 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.478G>A	p.Glu160Lys	missense	Exon 7 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.553G>A	p.Glu185Lys	missense	Exon 7 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74350

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Familial adenomatous polyposis 2 (2)
-	2	-	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.0075
Eigen_PC	Benign	0.056
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.73	N
PhyloP100		3.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.047	D
Polyphen		0.020	B
Vest4		0.65
MutPred		0.49		Gain of glycosylation at E188 (P = 0.0242)
MVP		0.92
MPC		0.41
ClinPred		0.96	D
GERP RS		3.1
PromoterAI		0.0084	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.65
Mutation Taster		=26/74	disease causing

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

Other links and lift over

dbSNP: rs1428261191; hg19: chr1-45798449; COSMIC: COSV58343702; COSMIC: COSV58343702;