rs1800566

chr16-69711242-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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 Benign (★). 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
• Clinical Significance: Benign criteria provided, single submitter P:1 B:1 O:3
• Conservation: PhyloP100: 9.29

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031418502).
• BP6: Variant 16-69711242-G-A is Benign according to our data. Variant chr16-69711242-G-A is described in ClinVar as [Benign]. Clinvar id is 16809.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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	UniProt
NQO1	NM_000903.3	c.559C>T	p.Pro187Ser	missense_variant	6/6	ENST00000320623.10
NQO1	NM_001025433.2	c.457C>T	p.Pro153Ser	missense_variant	5/5
NQO1	NM_001025434.2	c.445C>T	p.Pro149Ser	missense_variant	5/5
NQO1	NM_001286137.2	c.343C>T	p.Pro115Ser	missense_variant	4/4

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32896 AN: 151948 Hom.: 3881 Cov.: 32

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

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.: 33 AF XY: 0.208 AC XY: 150960 AN XY: 724570

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.: 32 AF XY: 0.223 AC XY: 16554 AN XY: 74316

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: Benign

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

Revision: criteria provided, single submitter

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, criteria provided, single submitter

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	T
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
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	T
MutationTaster	Benign	1.6e-9	P;P;P;P;P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-7.5	D;D;D;D;D;D
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	T
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

Other links and lift over

dbSNP: rs1800566; hg19: chr16-69745145; COSMIC: COSV57731060; COSMIC: COSV57731060;