chr16-69711242-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000903.3(NQO1):c.559C>T(p.Pro187Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,610,182 control chromosomes in the GnomAD database, including 37,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P187P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.22 ( 3888 hom., cov: 32)

Exomes 𝑓: 0.21 ( 33933 hom. )

Consequence

NQO1
NM_000903.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:2

Conservation

PhyloP100: 9.29

Variant links:

Genes affected

NQO1 (HGNC:2874): (NAD(P)H quinone dehydrogenase 1) This gene is a member of the NAD(P)H dehydrogenase (quinone) family and encodes a cytoplasmic 2-electron reductase. This FAD-binding protein forms homodimers and reduces quinones to hydroquinones. This protein's enzymatic activity prevents the one electron reduction of quinones that results in the production of radical species. Mutations in this gene have been associated with tardive dyskinesia (TD), an increased risk of hematotoxicity after exposure to benzene, and susceptibility to various forms of cancer. Altered expression of this protein has been seen in many tumors and is also associated with Alzheimer's disease (AD). Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

NQO1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031418502).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NQO1	NM_000903.3 link	c.559C>T	p.Pro187Ser	missense_variant	Exon 6 of 6	ENST00000320623.10	NP_000894.1	P15559-1
NQO1	NM_001025433.2 link	c.457C>T	p.Pro153Ser	missense_variant	Exon 5 of 5		NP_001020604.1	P15559-2
NQO1	NM_001025434.2 link	c.445C>T	p.Pro149Ser	missense_variant	Exon 5 of 5		NP_001020605.1	P15559-3
NQO1	NM_001286137.2 link	c.343C>T	p.Pro115Ser	missense_variant	Exon 4 of 4		NP_001273066.1	B4DLR8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NQO1	ENST00000320623.10 link	c.559C>T	p.Pro187Ser	missense_variant	Exon 6 of 6	1	NM_000903.3	ENSP00000319788.5		P15559-1

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

32896

AN:

151948

Hom.:

3881

Cov.:

show subpopulations

Gnomad AFR

AF:

0.186

Gnomad AMI

AF:

0.203

Gnomad AMR

AF:

0.328

Gnomad ASJ

AF:

0.179

Gnomad EAS

AF:

0.445

Gnomad SAS

AF:

0.333

Gnomad FIN

AF:

0.189

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.190

Gnomad OTH

AF:

0.237

GnomAD2 exomes

AF:

0.252

AC:

62641

AN:

248524

AF XY:

0.249

show subpopulations

Gnomad AFR exome

AF:

0.188

Gnomad AMR exome

AF:

0.391

Gnomad ASJ exome

AF:

0.184

Gnomad EAS exome

AF:

0.455

Gnomad FIN exome

AF:

0.182

Gnomad NFE exome

AF:

0.189

Gnomad OTH exome

AF:

0.230

GnomAD4 exome

AF:

0.206

AC:

300203

AN:

1458116

Hom.:

33933

Cov.:

AF XY:

0.208

AC XY:

150960

AN XY:

724570

show subpopulations

Gnomad4 AFR exome

AF:

0.183

AC:

6127

AN:

33428

Gnomad4 AMR exome

AF:

0.383

AC:

17086

AN:

44640

Gnomad4 ASJ exome

AF:

0.184

AC:

4798

AN:

26104

Gnomad4 EAS exome

AF:

0.415

AC:

16438

AN:

39588

Gnomad4 SAS exome

AF:

0.313

AC:

26943

AN:

86142

Gnomad4 FIN exome

AF:

0.179

AC:

9577

AN:

53374

Gnomad4 NFE exome

AF:

0.185

AC:

204605

AN:

1108870

Gnomad4 Remaining exome

AF:

0.219

AC:

13196

AN:

60264

Heterozygous variant carriers

11936

23872

35809

47745

59681

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

7460

14920

22380

29840

37300

<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:

0.217

AC:

32929

AN:

152066

Hom.:

3888

Cov.:

AF XY:

0.223

AC XY:

16554

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.186

AC:

0.18605

AN:

0.18605

Gnomad4 AMR

AF:

0.328

AC:

0.328311

AN:

0.328311

Gnomad4 ASJ

AF:

0.179

AC:

0.178571

AN:

0.178571

Gnomad4 EAS

AF:

0.445

AC:

0.445221

AN:

0.445221

Gnomad4 SAS

AF:

0.334

AC:

0.334094

AN:

0.334094

Gnomad4 FIN

AF:

0.189

AC:

0.188885

AN:

0.188885

Gnomad4 NFE

AF:

0.190

AC:

0.190101

AN:

0.190101

Gnomad4 OTH

AF:

0.236

AC:

0.236467

AN:

0.236467

Heterozygous variant carriers

1282

2564

3845

5127

6409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<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:

0.202

Hom.:

16440

Bravo

AF:

0.227

TwinsUK

AF:

0.183

AC:

677

ALSPAC

AF:

0.199

AC:

768

ESP6500AA

AF:

0.195

AC:

856

ESP6500EA

AF:

0.199

AC:

1709

ExAC

AF:

0.245

AC:

29705

Asia WGS

AF:

0.329

AC:

1142

AN:

3478

EpiCase

AF:

0.194

EpiControl

AF:

0.203

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

NQO1-related disorder

Uncertain:1Benign:1

Apr 03, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Benzene toxicity, susceptibility to

Benign:1

Jul 01, 2008

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

.;.;T;.;.;T

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.92

D;D;D;D;D;D

MetaRNN

Benign

0.0031

T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.7

.;.;L;.;.;.

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-7.5

D;D;D;D;D;D

REVEL

Uncertain

0.37

Sift

Benign

0.054

T;T;D;D;T;D

Sift4G

Benign

0.064

T;D;D;T;T;D

Polyphen

0.44, 1.0

.;.;B;.;D;.

Vest4

0.33

MPC

1.1

ClinPred

0.036

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.94

Mutation Taster

=47/53

polymorphism (auto)

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over