rs1553129230

Variant names:

• chr1-45332920-C-T
• rs1553129230
• NM_001128425.2:c.502G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_001048174.2(MUTYH):​c.418G>A​(p.Glu140Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. E140D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUTYH NM_001048174.2 missense, splice_region
• Scores: Splicing: ADA: 0.002830
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.51
• Publications: 0 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_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 62 uncertain in NM_001048174.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-45332918-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3400141.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

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.502G>A	p.Glu168Lys	missense splice_region	Exon 6 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.418G>A	p.Glu140Lys	missense splice_region	Exon 6 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.493G>A	p.Glu165Lys	missense splice_region	Exon 6 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.502G>A	p.Glu168Lys	missense splice_region	Exon 6 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.418G>A	p.Glu140Lys	missense splice_region	Exon 6 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.493G>A	p.Glu165Lys	missense splice_region	Exon 6 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 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	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.47		Gain of MoRF binding (P = 0.0116)
MVP		0.95
MPC		0.55
ClinPred		0.97	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.95
gMVP		0.66
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0028
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.10		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: rs1553129230; hg19: chr1-45798592;