1-45329355-C-T

Variant names:

• chr1-45329355-C-T
• rs3219497
• NM_001128425.2:c.1601G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001048174.2(MUTYH):​c.1517G>A​(p.Arg506Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,614,114 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R506P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (29 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (18 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21 O:1
• Conservation: PhyloP100: -1.11
• Publications: 18 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021564662).
• BP6: Variant 1-45329355-C-T is Benign according to our data. Variant chr1-45329355-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0102 (1558/152226) while in subpopulation AFR AF = 0.0352 (1460/41510). AF 95% confidence interval is 0.0337. There are 29 homozygotes in GnomAd4. There are 734 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 AD,AR gene

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.1601G>A	p.Arg534Gln	missense	Exon 16 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.1517G>A	p.Arg506Gln	missense	Exon 16 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.1592G>A	p.Arg531Gln	missense	Exon 16 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.1601G>A	p.Arg534Gln	missense	Exon 16 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.1517G>A	p.Arg506Gln	missense	Exon 16 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.1592G>A	p.Arg531Gln	missense	Exon 16 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1540 AN: 152108 Hom.: 28 Cov.: 31

Gnomad AFR AF: 0.0348

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00266 AC: 669 AN: 251496 AF XY: 0.00199

Gnomad AFR exome AF: 0.0377

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.00100 AC: 1464 AN: 1461888 Hom.: 18 Cov.: 31 AF XY: 0.000842 AC XY: 612 AN XY: 727248

African (AFR) AF: 0.0356 AC: 1193 AN: 33480

American (AMR) AF: 0.00174 AC: 78 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53420

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5766

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1112008

Other (OTH) AF: 0.00200 AC: 121 AN: 60396

GnomAD4 genome AF: 0.0102 AC: 1558 AN: 152226 Hom.: 29 Cov.: 31 AF XY: 0.00986 AC XY: 734 AN XY: 74422

African (AFR) AF: 0.0352 AC: 1460 AN: 41510

American (AMR) AF: 0.00497 AC: 76 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68018

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00424 Hom.: 21

Bravo AF: 0.0112

ESP6500AA AF: 0.0365 AC: 161

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00327 AC: 397

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (8)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	5	not provided (5)
-	-	2	Familial adenomatous polyposis 2 (2)
-	-	1	Carcinoma of colon (1)
-	-	1	Gastric cancer;C3272841:Familial adenomatous polyposis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	6.0
DANN	Benign	0.89
DEOGEN2	Benign	0.045	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L
PhyloP100		-1.1
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.11
Sift	Benign	0.24	T
Sift4G	Benign	0.20	T
Polyphen		0.026	B
Vest4		0.11
MVP		0.48
MPC		0.13
ClinPred		0.0017	T
GERP RS		-3.6
Varity_R		0.045
gMVP		0.15
Mutation Taster		=97/3	polymorphism

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: rs3219497; hg19: chr1-45795027; COSMIC: COSV104641846;