1-45331833-C-G

Variant names:

• chr1-45331833-C-G
• rs3219489
• NM_001128425.2:c.1014G>C

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.930G>C​(p.Gln310His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,603,502 control chromosomes in the GnomAD database, including 56,797 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q310R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (5852 hom., cov: 33)
  • Exomes 𝑓: 0.26 (50945 hom.)
• Consequence: MUTYH NM_001048174.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22 O:1
• Conservation: PhyloP100: -0.265
• Publications: 182 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010225773).
• BP6: Variant 1-45331833-C-G is Benign according to our data. Variant chr1-45331833-C-G is described in ClinVar as Benign. ClinVar VariationId is 41767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

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.1014G>C	p.Gln338His	missense	Exon 12 of 16	NP_001121897.1	E5KP25
	MUTYH	NM_001048174.2	MANE Select	c.930G>C	p.Gln310His	missense	Exon 12 of 16	NP_001041639.1	Q9UIF7-6
	MUTYH	NM_012222.3		c.1005G>C	p.Gln335His	missense	Exon 12 of 16	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.1014G>C	p.Gln338His	missense	Exon 12 of 16	ENSP00000518552.2	E5KP25
	MUTYH	ENST00000456914.7	TSL:1 MANE Select	c.930G>C	p.Gln310His	missense	Exon 12 of 16	ENSP00000407590.2	Q9UIF7-6
	MUTYH	ENST00000372098.7	TSL:1	c.1005G>C	p.Gln335His	missense	Exon 12 of 16	ENSP00000361170.3	Q9UIF7-1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40958 AN: 152016 Hom.: 5824 Cov.: 33

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.297

GnomAD2 exomes AF: 0.290 AC: 67377 AN: 232316 AF XY: 0.277

Gnomad AFR exome AF: 0.263

Gnomad AMR exome AF: 0.488

Gnomad ASJ exome AF: 0.263

Gnomad EAS exome AF: 0.397

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.244

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.260 AC: 377531 AN: 1451368 Hom.: 50945 Cov.: 42 AF XY: 0.257 AC XY: 185520 AN XY: 721162

African (AFR) AF: 0.266 AC: 8835 AN: 33194

American (AMR) AF: 0.477 AC: 20523 AN: 43026

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 6710 AN: 25756

East Asian (EAS) AF: 0.420 AC: 16507 AN: 39306

South Asian (SAS) AF: 0.233 AC: 19899 AN: 85350

European-Finnish (FIN) AF: 0.228 AC: 11904 AN: 52316

Middle Eastern (MID) AF: 0.292 AC: 1643 AN: 5630

European-Non Finnish (NFE) AF: 0.249 AC: 275322 AN: 1106868

Other (OTH) AF: 0.270 AC: 16188 AN: 59922

GnomAD4 genome AF: 0.270 AC: 41017 AN: 152134 Hom.: 5852 Cov.: 33 AF XY: 0.270 AC XY: 20054 AN XY: 74356

African (AFR) AF: 0.263 AC: 10933 AN: 41514

American (AMR) AF: 0.401 AC: 6123 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 909 AN: 3470

East Asian (EAS) AF: 0.412 AC: 2127 AN: 5162

South Asian (SAS) AF: 0.238 AC: 1147 AN: 4824

European-Finnish (FIN) AF: 0.215 AC: 2275 AN: 10594

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

European-Non Finnish (NFE) AF: 0.243 AC: 16532 AN: 67978

Other (OTH) AF: 0.305 AC: 642 AN: 2108

Alfa AF: 0.250 Hom.: 1622

Bravo AF: 0.287

TwinsUK AF: 0.249 AC: 922

ALSPAC AF: 0.255 AC: 981

ESP6500AA AF: 0.264 AC: 1161

ESP6500EA AF: 0.249 AC: 2143

ExAC AF: 0.268 AC: 32463

Asia WGS AF: 0.359 AC: 1247 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (9)
-	-	4	Familial adenomatous polyposis 2 (4)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	4	not provided (4)
-	-	1	Carcinoma of colon (1)
-	-	1	Familial multiple polyposis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.80
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0010	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		-0.27
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.043
Sift	Benign	0.17	T
Sift4G	Benign	0.12	T
Polyphen		0.65	P
Vest4		0.13
MutPred		0.12		Loss of sheet (P = 0.0457)
MPC		0.13
ClinPred		0.016	T
GERP RS		1.3
PromoterAI		-0.00020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.51
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs3219489; hg19: chr1-45797505; COSMIC: COSV58343790; COSMIC: COSV58343790;