rs138089183

Variant names:

• chr1-45332174-G-A
• rs138089183
• NM_001128425.2:c.925C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_001048174.2(MUTYH):​c.841C>T​(p.Arg281Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000694 in 1,614,204 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R281H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00072 (1 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:19 B:5 O:1
• Conservation: PhyloP100: -0.212
• Publications: 44 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: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 66 uncertain in NM_001048174.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.059933275).

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.925C>T	p.Arg309Cys	missense	Exon 10 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.841C>T	p.Arg281Cys	missense	Exon 10 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.916C>T	p.Arg306Cys	missense	Exon 10 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.925C>T	p.Arg309Cys	missense	Exon 10 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.841C>T	p.Arg281Cys	missense	Exon 10 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.916C>T	p.Arg306Cys	missense	Exon 10 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes AF: 0.000466 AC: 71 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000454 AC: 114 AN: 251334 AF XY: 0.000442

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000889

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000718 AC: 1050 AN: 1461880 Hom.: 1 Cov.: 36 AF XY: 0.000714 AC XY: 519 AN XY: 727244

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53412

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000883 AC: 982 AN: 1112008

Other (OTH) AF: 0.000679 AC: 41 AN: 60396

GnomAD4 genome AF: 0.000466 AC: 71 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74476

African (AFR) AF: 0.000144 AC: 6 AN: 41572

American (AMR) AF: 0.000327 AC: 5 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000644 Hom.: 1

Bravo AF: 0.000431

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000436 AC: 53

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	6	1	Familial adenomatous polyposis 2 (8)
-	5	1	not provided (6)
-	2	2	Hereditary cancer-predisposing syndrome (4)
-	3	-	not specified (3)
-	1	-	Familial colorectal cancer type X (1)
-	1	-	Gastric cancer;C3272841:Familial adenomatous polyposis 2 (1)
-	-	1	Hereditary cancer (1)
-	1	-	MUTYH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	19
DANN	Benign	0.78
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.060	T
MetaSVM	Uncertain	-0.042	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.21
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.59
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		0.054	B
Vest4		0.20
MVP		0.82
MPC		0.16
ClinPred		0.017	T
GERP RS		-2.1
PromoterAI		0.025	Neutral
Varity_R		0.13
gMVP		0.67
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138089183; hg19: chr1-45797846;