rs3219485

Variant names:

• chr1-45334361-T-C
• rs3219485
• NM_001128425.2:c.157+30A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001128425.2(MUTYH):​c.157+30A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 1,613,254 control chromosomes in the GnomAD database, including 987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (47 hom., cov: 32)
  • Exomes 𝑓: 0.034 (940 hom.)
• Consequence: MUTYH NM_001128425.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.413
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-45334361-T-C is Benign according to our data. Variant chr1-45334361-T-C is described in ClinVar as Benign. ClinVar VariationId is 257528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0224 (3406/152282) while in subpopulation NFE AF = 0.0365 (2481/68016). AF 95% confidence interval is 0.0353. There are 47 homozygotes in GnomAd4. There are 1581 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 47 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	NM_001128425.2	MANE Plus Clinical	c.157+30A>G		intron	N/A	NP_001121897.1
	MUTYH	NM_001048174.2	MANE Select	c.115+30A>G		intron	N/A	NP_001041639.1
	MUTYH	NM_012222.3		c.157+30A>G		intron	N/A	NP_036354.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUTYH	ENST00000710952.2	MANE Plus Clinical	c.157+30A>G		intron	N/A	ENSP00000518552.2
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.115+30A>G		intron	N/A	ENSP00000407590.2
	MUTYH	ENST00000372098.7	TSL:1	c.157+30A>G		intron	N/A	ENSP00000361170.3

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3409 AN: 152164 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.00637

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00952

Gnomad FIN AF: 0.0239

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0365

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0236 AC: 5924 AN: 251230 AF XY: 0.0242

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.00798

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0278

Gnomad NFE exome AF: 0.0379

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.0335 AC: 48998 AN: 1460972 Hom.: 940 Cov.: 31 AF XY: 0.0328 AC XY: 23874 AN XY: 726808

African (AFR) AF: 0.00457 AC: 153 AN: 33470

American (AMR) AF: 0.00941 AC: 421 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 520 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.0113 AC: 971 AN: 86226

European-Finnish (FIN) AF: 0.0307 AC: 1631 AN: 53104

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5762

European-Non Finnish (NFE) AF: 0.0394 AC: 43759 AN: 1111534

Other (OTH) AF: 0.0251 AC: 1513 AN: 60348

GnomAD4 genome AF: 0.0224 AC: 3406 AN: 152282 Hom.: 47 Cov.: 32 AF XY: 0.0212 AC XY: 1581 AN XY: 74466

African (AFR) AF: 0.00635 AC: 264 AN: 41568

American (AMR) AF: 0.0145 AC: 222 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00953 AC: 46 AN: 4826

European-Finnish (FIN) AF: 0.0239 AC: 254 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0365 AC: 2481 AN: 68016

Other (OTH) AF: 0.0198 AC: 42 AN: 2116

Alfa AF: 0.0329 Hom.: 143

Bravo AF: 0.0214

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Familial adenomatous polyposis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.8
DANN	Benign	0.45
PhyloP100		0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs3219485; hg19: chr1-45800033; COSMIC: COSV62743540;