rs77542170

Variant names:

• chr1-45332088-T-C
• rs77542170
• NM_001128425.2:c.934-2A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 12P and 6B. PVS1 PS3 BP6 BS1 BS2_Supporting

The NM_001048174.2(MUTYH):​c.850-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000561 in 1,614,184 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001553529: Two independent studies have shown the MUTYH c.934-2A>G variant results in an aberrant mRNA transcript which retains intron 10, has a premature stop codon in exon 11, and encodes a truncated protein (Tao 2004 and Taki 2015). Further, in vitro expression studies demonstrate that, if translated, the variant protein is not localized in the nucleus like the wild type protein, suggesting insufficient ability of the variant protein to repair nuclear DNA (Tao 2004).".

• Frequency:
  • Genomes: 𝑓 0.00054 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (13 hom.)
• Consequence: MUTYH NM_001048174.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:7 B:8 O:1
• Conservation: PhyloP100: 3.12
• Publications: 78 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 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001553529: Two independent studies have shown the MUTYH c.934-2A>G variant results in an aberrant mRNA transcript which retains intron 10, has a premature stop codon in exon 11, and encodes a truncated protein (Tao 2004 and Taki 2015). Further, in vitro expression studies demonstrate that, if translated, the variant protein is not localized in the nucleus like the wild type protein, suggesting insufficient ability of the variant protein to repair nuclear DNA (Tao 2004).
• BP6: Variant 1-45332088-T-C is Benign according to our data. Variant chr1-45332088-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41766.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000545 (83/152294) while in subpopulation EAS AF = 0.0156 (81/5184). AF 95% confidence interval is 0.0129. There are 1 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.934-2A>G		splice_acceptor intron	N/A	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.850-2A>G		splice_acceptor intron	N/A	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.925-2A>G		splice_acceptor intron	N/A	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.934-2A>G		splice_acceptor intron	N/A	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.850-2A>G		splice_acceptor intron	N/A	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.925-2A>G		splice_acceptor intron	N/A	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152176 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00113 AC: 285 AN: 251466 AF XY: 0.00113

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0152

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000563 AC: 823 AN: 1461890 Hom.: 13 Cov.: 36 AF XY: 0.000546 AC XY: 397 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: 0.0190 AC: 755 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 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: 0.00000360 AC: 4 AN: 1112008

Other (OTH) AF: 0.000729 AC: 44 AN: 60396

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152294 Hom.: 1 Cov.: 33 AF XY: 0.000685 AC XY: 51 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15306

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

East Asian (EAS) AF: 0.0156 AC: 81 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000613 Hom.: 3

Bravo AF: 0.000453

ExAC AF: 0.00102 AC: 124

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	3	2	Familial adenomatous polyposis 2 (7)
-	3	1	not provided (4)
-	1	2	not specified (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
1	-	-	Carcinoma of colon (1)
1	-	-	Gastric cancer (1)
-	-	1	MUTYH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	27
DANN	Benign	0.96
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		3.1
GERP RS		5.3
PromoterAI		0.073	Neutral
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: -11
DS_AL_spliceai		0.95		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs77542170; hg19: chr1-45797760;