1-45329412-G-A

Variant names:

• chr1-45329412-G-A
• rs140118273
• NM_001128425.2:c.1544C>T

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.1460C>T​(p.Ser487Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,614,140 control chromosomes in the GnomAD database, including 152 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. S487A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0098 (12 hom., cov: 31)
  • Exomes 𝑓: 0.011 (140 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27 O:1
• Conservation: PhyloP100: 1.76
• Publications: 47 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=0.004083574).
• BP6: Variant 1-45329412-G-A is Benign according to our data. Variant chr1-45329412-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00975 (1485/152264) while in subpopulation NFE AF = 0.0118 (800/68018). AF 95% confidence interval is 0.0111. There are 12 homozygotes in GnomAd4. There are 693 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR,AD 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.1544C>T	p.Ser515Phe	missense	Exon 16 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.1460C>T	p.Ser487Phe	missense	Exon 16 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.1535C>T	p.Ser512Phe	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.1544C>T	p.Ser515Phe	missense	Exon 16 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.1460C>T	p.Ser487Phe	missense	Exon 16 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.1535C>T	p.Ser512Phe	missense	Exon 16 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes AF: 0.00977 AC: 1487 AN: 152146 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.00816

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00995

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00841 AC: 2115 AN: 251444 AF XY: 0.00834

Gnomad AFR exome AF: 0.00738

Gnomad AMR exome AF: 0.00688

Gnomad ASJ exome AF: 0.0234

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00476

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.0112 AC: 16371 AN: 1461876 Hom.: 140 Cov.: 31 AF XY: 0.0108 AC XY: 7837 AN XY: 727238

African (AFR) AF: 0.00944 AC: 316 AN: 33480

American (AMR) AF: 0.00700 AC: 313 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0232 AC: 606 AN: 26134

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

South Asian (SAS) AF: 0.00253 AC: 218 AN: 86256

European-Finnish (FIN) AF: 0.00515 AC: 275 AN: 53420

Middle Eastern (MID) AF: 0.0525 AC: 303 AN: 5766

European-Non Finnish (NFE) AF: 0.0123 AC: 13643 AN: 1112000

Other (OTH) AF: 0.0115 AC: 697 AN: 60396

GnomAD4 genome AF: 0.00975 AC: 1485 AN: 152264 Hom.: 12 Cov.: 31 AF XY: 0.00931 AC XY: 693 AN XY: 74460

African (AFR) AF: 0.00816 AC: 339 AN: 41548

American (AMR) AF: 0.00987 AC: 151 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 100 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4828

European-Finnish (FIN) AF: 0.00339 AC: 36 AN: 10614

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0118 AC: 800 AN: 68018

Other (OTH) AF: 0.0156 AC: 33 AN: 2114

Alfa AF: 0.0110 Hom.: 29

Bravo AF: 0.0106

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0126 AC: 108

ExAC AF: 0.00787 AC: 956

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0130

EpiControl AF: 0.0122

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (12)
-	-	6	Hereditary cancer-predisposing syndrome (6)
-	-	5	not provided (5)
-	-	4	Familial adenomatous polyposis 2 (4)
-	-	1	Familial multiple polyposis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.068	N
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.8
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.23
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.034	D
Polyphen		0.14	B
Vest4		0.20
MVP		0.59
MPC		0.18
ClinPred		0.0071	T
GERP RS		0.17
Varity_R		0.041
gMVP		0.22
Mutation Taster		=99/1	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: rs140118273; hg19: chr1-45795084; COSMIC: COSV58344455; COSMIC: COSV58344455;