rs3219490

Variant names:

• chr1-45331583-G-A
• rs3219490
• NM_001128425.2:c.1187-27C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

The NM_001048174.2(MUTYH):​c.1103-27C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,613,578 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (17 hom.)
• Consequence: MUTYH NM_001048174.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.676
• Publications: 6 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-45331583-G-A is Benign according to our data. Variant chr1-45331583-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 801475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 17 AD,AR 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.1187-27C>T		intron	N/A	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.1103-27C>T		intron	N/A	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.1178-27C>T		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.1187-27C>T		intron	N/A	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.1103-27C>T		intron	N/A	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.1178-27C>T		intron	N/A	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 456 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00492

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00365 AC: 908 AN: 248612 AF XY: 0.00380

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00379

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000525

Gnomad NFE exome AF: 0.00577

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.00438 AC: 6406 AN: 1461218 Hom.: 17 Cov.: 33 AF XY: 0.00443 AC XY: 3222 AN XY: 726876

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.00295 AC: 132 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00363 AC: 95 AN: 26136

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

South Asian (SAS) AF: 0.00242 AC: 209 AN: 86258

European-Finnish (FIN) AF: 0.000455 AC: 24 AN: 52782

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.00506 AC: 5626 AN: 1111986

Other (OTH) AF: 0.00439 AC: 265 AN: 60386

GnomAD4 genome AF: 0.00299 AC: 456 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.00281 AC XY: 209 AN XY: 74506

African (AFR) AF: 0.00103 AC: 43 AN: 41588

American (AMR) AF: 0.00268 AC: 41 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00492 AC: 335 AN: 68036

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00447 Hom.: 0

Bravo AF: 0.00320

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Familial adenomatous polyposis 2 (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	MUTYH-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.5
DANN	Benign	0.55
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3219490; hg19: chr1-45797255; COSMIC: COSV104641844;