chr16-69711242-G-A

Position:

chr16-69711242-G-A

Variant summary

Our verdict is Benign. Variant got -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 Conflicting classifications of pathogenicity,risk factor (no stars).

Frequency

Genomes: 𝑓 0.22 ( 3888 hom., cov: 32)

Exomes 𝑓: 0.21 ( 33933 hom. )

Consequence

NQO1
NM_000903.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; risk factor no assertion criteria provided P:1B:1O:3

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 made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein
NQO1	NM_000903.3 linkuse as main transcript	c.559C>T	p.Pro187Ser	missense_variant	6/6	ENST00000320623.10	NP_000894.1
NQO1	NM_001025433.2 linkuse as main transcript	c.457C>T	p.Pro153Ser	missense_variant	5/5		NP_001020604.1
NQO1	NM_001025434.2 linkuse as main transcript	c.445C>T	p.Pro149Ser	missense_variant	5/5		NP_001020605.1
NQO1	NM_001286137.2 linkuse as main transcript	c.343C>T	p.Pro115Ser	missense_variant	4/4		NP_001273066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NQO1	ENST00000320623.10 linkuse as main transcript	c.559C>T	p.Pro187Ser	missense_variant	6/6	1	NM_000903.3	ENSP00000319788	P1	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

GnomAD3 exomes

AF:

0.252

AC:

62641

AN:

248524

Hom.:

9185

AF XY:

0.249

AC XY:

33426

AN XY:

134474

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 SAS exome

AF:

0.314

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

Gnomad4 AMR exome

AF:

0.383

Gnomad4 ASJ exome

AF:

0.184

Gnomad4 EAS exome

AF:

0.415

Gnomad4 SAS exome

AF:

0.313

Gnomad4 FIN exome

AF:

0.179

Gnomad4 NFE exome

AF:

0.185

Gnomad4 OTH exome

AF:

0.219

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

Gnomad4 AMR

AF:

0.328

Gnomad4 ASJ

AF:

0.179

Gnomad4 EAS

AF:

0.445

Gnomad4 SAS

AF:

0.334

Gnomad4 FIN

AF:

0.189

Gnomad4 NFE

AF:

0.190

Gnomad4 OTH

AF:

0.236

Alfa

AF:

0.202

Hom.:

8591

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: Conflicting classifications of pathogenicity; risk factor

Submissions summary: Pathogenic:1Benign:1Other:3

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Breast cancer, post-chemotherapy poor survival in

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2008

- -

NQO1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

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). -

Lung carcinoma

Other:1

not provided, no classification provided

literature only

Database of Curated Mutations (DoCM)

Mar 10, 2016

- -

Leukemia, post-chemotherapy, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 01, 2008

- -

Benzene toxicity, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 01, 2008

- -

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;.;.;.

MutationTaster

Benign

1.6e-9

P;P;P;P;P;P

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

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