dbSNP rs1131341: NQO1:p.Arg139Trp (chr16-69714966-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000903.3(NQO1):c.415C>T(p.Arg139Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0381 in 1,608,954 control chromosomes in the GnomAD database, including 1,445 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.026 ( 73 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1372 hom. )

Consequence

NQO1
NM_000903.3 missense, splice_region

Scores

Splicing: ADA: 0.8539

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.40

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029577315).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.054 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NQO1	NM_000903.3 link	c.415C>T	p.Arg139Trp	missense_variant, splice_region_variant	Exon 4 of 6	ENST00000320623.10	NP_000894.1	P15559-1
NQO1	NM_001025433.2 link	c.415C>T	p.Arg139Trp	missense_variant, splice_region_variant	Exon 4 of 5		NP_001020604.1	P15559-2
NQO1	NM_001025434.2 link	c.304-1837C>T		intron_variant	Intron 3 of 4		NP_001020605.1	P15559-3
NQO1	NM_001286137.2 link	c.303+3157C>T		intron_variant	Intron 3 of 3		NP_001273066.1	B4DLR8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NQO1	ENST00000320623.10 link	c.415C>T	p.Arg139Trp	missense_variant, splice_region_variant	Exon 4 of 6	1	NM_000903.3	ENSP00000319788.5		P15559-1

Frequencies

GnomAD3 genomes

AF:

0.0260

AC:

3951

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0198

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.0272

Gnomad SAS

AF:

0.0592

Gnomad FIN

AF:

0.0102

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0371

Gnomad OTH

AF:

0.0298

GnomAD3 exomes

AF:

0.0320

AC:

8052

AN:

251392

Hom.:

182

AF XY:

0.0349

AC XY:

4737

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00954

Gnomad AMR exome

AF:

0.0145

Gnomad ASJ exome

AF:

0.0344

Gnomad EAS exome

AF:

0.0259

Gnomad SAS exome

AF:

0.0622

Gnomad FIN exome

AF:

0.0114

Gnomad NFE exome

AF:

0.0370

Gnomad OTH exome

AF:

0.0357

GnomAD4 exome

AF:

0.0394

AC:

57403

AN:

1456798

Hom.:

1372

Cov.:

AF XY:

0.0401

AC XY:

29079

AN XY:

725016

show subpopulations

Gnomad4 AFR exome

AF:

0.00773

Gnomad4 AMR exome

AF:

0.0148

Gnomad4 ASJ exome

AF:

0.0330

Gnomad4 EAS exome

AF:

0.0236

Gnomad4 SAS exome

AF:

0.0597

Gnomad4 FIN exome

AF:

0.0129

Gnomad4 NFE exome

AF:

0.0417

Gnomad4 OTH exome

AF:

0.0395

GnomAD4 genome

AF:

0.0261

AC:

3964

AN:

152156

Hom.:

Cov.:

AF XY:

0.0254

AC XY:

1888

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0104

Gnomad4 AMR

AF:

0.0198

Gnomad4 ASJ

AF:

0.0271

Gnomad4 EAS

AF:

0.0273

Gnomad4 SAS

AF:

0.0597

Gnomad4 FIN

AF:

0.0102

Gnomad4 NFE

AF:

0.0371

Gnomad4 OTH

AF:

0.0342

Alfa

AF:

0.0363

Hom.:

199

Bravo

AF:

0.0253

TwinsUK

AF:

0.0434

AC:

161

ALSPAC

AF:

0.0381

AC:

147

ESP6500AA

AF:

0.0123

AC:

ESP6500EA

AF:

0.0397

AC:

341

ExAC

AF:

0.0327

AC:

3971

Asia WGS

AF:

0.0610

AC:

213

AN:

3478

EpiCase

AF:

0.0401

EpiControl

AF:

0.0376

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

.;T;T

Eigen

Benign

0.0045

Eigen_PC

Benign

0.028

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.81

T;D;D

MetaRNN

Benign

0.0030

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M;.

PrimateAI

Benign

0.19

PROVEAN

Uncertain

-2.4

N;D;D

REVEL

Benign

0.053

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.021

.;B;.

Vest4

0.36

MPC

0.96

ClinPred

0.030

GERP RS

2.8

Varity_R

0.50

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.85

dbscSNV1_RF

Pathogenic

0.86

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over