chr1-45334510-G-C

Variant names:

• chr1-45334510-G-C
• rs587780747
• NM_001128425.2:c.38C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_001128425.2(MUTYH):​c.38C>G​(p.Ala13Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A13T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUTYH NM_001128425.2 missense, splice_region
• Scores: Splicing: ADA: 0.00005851
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Orphanet, 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: AR, AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 63 uncertain in NM_001128425.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061994284).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128425.2. 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.38C>G	p.Ala13Gly	missense splice_region	Exon 2 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.-5C>G		splice_region	Exon 2 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_001048174.2	MANE Select	c.-5C>G		5_prime_UTR	Exon 2 of 16	NP_001041639.1	Q9UIF7-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	ENST00000710952.2	MANE Plus Clinical	c.38C>G	p.Ala13Gly	missense splice_region	Exon 2 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.-5C>G		splice_region	Exon 2 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.38C>G	p.Ala13Gly	missense splice_region	Exon 2 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.1
DANN	Benign	0.95
DEOGEN2	Benign	0.081	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.90	L
PhyloP100		-1.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.026
Sift	Benign	0.035	D
Sift4G	Benign	0.11	T
Polyphen		0.019	B
Vest4		0.25
MutPred		0.26		Loss of helix (P = 0.0444)
MVP		0.34
MPC		0.12
ClinPred		0.11	T
GERP RS		-3.9
Varity_R		0.043
gMVP		0.22
Mutation Taster		=297/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000059
dbscSNV1_RF	Benign	0.026
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: rs587780747; hg19: chr1-45800182;