1-45331833-C-G

Variant names:

Variant summary

Our verdict is . The variant received -14 classification points (ACMG Germline Pathogenicity v2019): 0P and 14B. BA1BP4_ModerateBP6_Strong

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 cumulative frequency of 0.261 (AC=418,548) in the gnomAD database across 1,603,502 control chromosomes, including 56,797 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.472. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.Q310E: Uncertain_significance (ClinVar VariationId 4112922, 1 star); p.Q310H: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 492713); p.Q310K: Uncertain_significance (ClinVar VariationId 4112921, 1 star); p.Q310L: Benign (ClinVar VariationId 485901, 1 star); p.Q310P: Uncertain_significance (ClinVar VariationId 4112923, 1 star); p.Q310= (synonymous): Likely_benign (ClinVar VariationId 1740087, 1 star); p.Q310R: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 127836); p.Q310R: Benign/Likely_benign (ClinVar VariationId 142590, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.27 ( 5852 hom., cov: 33)

Exomes 𝑓: 0.26 ( 50945 hom. )

Consequence

MUTYH
NM_001048174.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:22O:1

Conservation

PhyloP100: -0.265

Publications

182 publications found

Variant links:

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), G2P, Genomics England PanelApp, Orphanet, ClinGen
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

MUTYH links:

ENSG00000288208 (HGNC:):

ENSG00000288208 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001048174.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -14 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4715 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001048174.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

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

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.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.257

AC XY:

185520

AN XY:

721162

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

18127

36253

54380

72506

90633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9744

19488

29232

38976

48720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.270

AC:

41017

AN:

152134

Hom.:

5852

Cov.:

AF XY:

0.270

AC XY:

20054

AN XY:

74356

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.243

AC:

16532

AN:

67978

Other (OTH)

AF:

0.305

AC:

642

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1552

3103

4655

6206

7758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

422

844

1266

1688

2110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.250

Hom.:

1622

Bravo

AF:

0.287

Asia WGS

AF:

0.359

AC:

1247

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.457

AC:

56071

AN:

122724

Turkish Variome

AF:

0.261

AC:

1701

AN:

6524

Hom.:

239

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.376

AC:

3373

AN:

8960

Hom.:

613

ABraOM SABE-WGS-1171

AF:

0.308

AC:

721

AN:

2342

Hom.:

120

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

Familial adenomatous polyposis 2 (4)

Hereditary cancer-predisposing syndrome (4)

not provided (4)

Carcinoma of colon (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

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.086

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0010

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.7

PhyloP100

-0.27

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.0

REVEL

Benign

0.043

Sift

Benign

0.17

Sift4G

Benign

0.12

PromoterAI

-0.00020

Neutral

(source)

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)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over