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rs1800566

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

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

Scores

2
7
6

Clinical Significance

Benign criteria provided, single submitter 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]

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ACMG classification

Classification made for transcript

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
NQO1NM_000903.3 linkuse as main transcriptc.559C>T p.Pro187Ser missense_variant 6/6 ENST00000320623.10
NQO1NM_001025433.2 linkuse as main transcriptc.457C>T p.Pro153Ser missense_variant 5/5
NQO1NM_001025434.2 linkuse as main transcriptc.445C>T p.Pro149Ser missense_variant 5/5
NQO1NM_001286137.2 linkuse as main transcriptc.343C>T p.Pro115Ser missense_variant 4/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NQO1ENST00000320623.10 linkuse as main transcriptc.559C>T p.Pro187Ser missense_variant 6/61 NM_000903.3 P1P15559-1

Frequencies

GnomAD3 genomes
AF:
0.216
AC:
32896
AN:
151948
Hom.:
3881
Cov.:
32
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.:
33
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.:
32
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: Benign
Submissions summary: Pathogenic:1Benign:1Other:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Breast cancer, post-chemotherapy poor survival in Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 2008- -
NQO1-related condition Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 17, 2019This 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 providedliterature onlyDatabase of Curated Mutations (DoCM)Mar 10, 2016- -
Leukemia, post-chemotherapy, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJul 01, 2008- -
Benzene toxicity, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJul 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

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

Other links and lift over

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