rs1439243449

Variant names:

• chr1-45329338-C-T
• rs1439243449
• NM_001128425.2:c.1618G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001048174.2(MUTYH):​c.1534G>A​(p.Asp512Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. D512E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.432
• Publications: 1 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20646682).
• BP6: Variant 1-45329338-C-T is Benign according to our data. Variant chr1-45329338-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 492027.

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.1618G>A	p.Asp540Asn	missense	Exon 16 of 16	NP_001121897.1
	MUTYH	NM_001048174.2	MANE Select	c.1534G>A	p.Asp512Asn	missense	Exon 16 of 16	NP_001041639.1
	MUTYH	NM_012222.3		c.1609G>A	p.Asp537Asn	missense	Exon 16 of 16	NP_036354.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	ENST00000710952.2	MANE Plus Clinical	c.1618G>A	p.Asp540Asn	missense	Exon 16 of 16	ENSP00000518552.2
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.1534G>A	p.Asp512Asn	missense	Exon 16 of 16	ENSP00000407590.2
	MUTYH	ENST00000372098.7	TSL:1	c.1609G>A	p.Asp537Asn	missense	Exon 16 of 16	ENSP00000361170.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251496 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 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: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Familial adenomatous polyposis 2 (2)
-	1	1	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.43
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.88	P
Vest4		0.18
MutPred		0.13		Gain of MoRF binding (P = 0.0394)
MVP		0.77
MPC		0.11
ClinPred		0.66	D
GERP RS		3.8
Varity_R		0.21
gMVP		0.40
Mutation Taster		=92/8	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: rs1439243449; hg19: chr1-45795010; COSMIC: COSV100588172;