rs3219472

Variant names:

• chr1-45338378-C-T
• rs3219472
• NM_001048174.2:c.-7+1521G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001048174.2(MUTYH):​c.-7+1521G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 461,784 control chromosomes in the GnomAD database, including 16,857 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5580 hom., cov: 32)
  • Exomes 𝑓: 0.26 (11277 hom.)
• Consequence: MUTYH NM_001048174.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0170
• Publications: 18 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=-0.88).
• BP6: Variant 1-45338378-C-T is Benign according to our data. Variant chr1-45338378-C-T is described in ClinVar as Benign. ClinVar VariationId is 1260538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.-7+1521G>A		intron_variant	Intron 1 of 15	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.-7+1521G>A		intron_variant	Intron 1 of 15	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.541-3867G>A		intron_variant	Intron 5 of 20			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39986 AN: 152052 Hom.: 5557 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.293

GnomAD4 exome AF: 0.259 AC: 80163 AN: 309614 Hom.: 11277 Cov.: 0 AF XY: 0.252 AC XY: 41705 AN XY: 165284

African (AFR) AF: 0.244 AC: 2528 AN: 10380

American (AMR) AF: 0.452 AC: 9247 AN: 20458

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 2782 AN: 10960

East Asian (EAS) AF: 0.350 AC: 6898 AN: 19712

South Asian (SAS) AF: 0.227 AC: 11313 AN: 49826

European-Finnish (FIN) AF: 0.221 AC: 2121 AN: 9616

Middle Eastern (MID) AF: 0.271 AC: 349 AN: 1286

European-Non Finnish (NFE) AF: 0.237 AC: 40286 AN: 169942

Other (OTH) AF: 0.266 AC: 4639 AN: 17434

GnomAD4 genome AF: 0.263 AC: 40035 AN: 152170 Hom.: 5580 Cov.: 32 AF XY: 0.263 AC XY: 19535 AN XY: 74400

African (AFR) AF: 0.249 AC: 10352 AN: 41504

American (AMR) AF: 0.400 AC: 6128 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 902 AN: 3470

East Asian (EAS) AF: 0.365 AC: 1889 AN: 5178

South Asian (SAS) AF: 0.233 AC: 1123 AN: 4824

European-Finnish (FIN) AF: 0.208 AC: 2203 AN: 10590

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16478 AN: 67978

Other (OTH) AF: 0.298 AC: 631 AN: 2114

Alfa AF: 0.257 Hom.: 14284

Bravo AF: 0.280

Asia WGS AF: 0.339 AC: 1177 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.9
DANN	Benign	0.64
PhyloP100		0.017
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: rs3219472; hg19: chr1-45804050; COSMIC: COSV62744225; COSMIC: COSV62744225;