rs1131341

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R139L) has been classified as Uncertain significance.

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

Publications

103 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000903.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NQO1	NM_000903.3	MANE Select	c.415C>T	p.Arg139Trp	missense splice_region	Exon 4 of 6	NP_000894.1	P15559-1
NQO1	NM_001025433.2		c.415C>T	p.Arg139Trp	missense splice_region	Exon 4 of 5	NP_001020604.1	P15559-2
NQO1	NM_001025434.2		c.304-1837C>T		intron	N/A	NP_001020605.1	P15559-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NQO1	ENST00000320623.10	TSL:1 MANE Select	c.415C>T	p.Arg139Trp	missense splice_region	Exon 4 of 6	ENSP00000319788.5	P15559-1
NQO1	ENST00000564043.1	TSL:1	c.352C>T	p.Arg118Trp	missense splice_region	Exon 4 of 6	ENSP00000455020.1	H3BNV2
NQO1	ENST00000379047.7	TSL:1	c.415C>T	p.Arg139Trp	missense splice_region	Exon 4 of 5	ENSP00000368335.3	P15559-2

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

GnomAD2 exomes

AF:

0.0320

AC:

8052

AN:

251392

AF XY:

0.0349

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 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

African (AFR)

AF:

0.00773

AC:

258

AN:

33370

American (AMR)

AF:

0.0148

AC:

661

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0330

AC:

862

AN:

26086

East Asian (EAS)

AF:

0.0236

AC:

936

AN:

39654

South Asian (SAS)

AF:

0.0597

AC:

5141

AN:

86154

European-Finnish (FIN)

AF:

0.0129

AC:

690

AN:

53294

Middle Eastern (MID)

AF:

0.0486

AC:

280

AN:

5762

European-Non Finnish (NFE)

AF:

0.0417

AC:

46200

AN:

1107602

Other (OTH)

AF:

0.0395

AC:

2375

AN:

60184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

2614

5228

7841

10455

13069

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1774

3548

5322

7096

8870

<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:

0.0261

AC:

3964

AN:

152156

Hom.:

Cov.:

AF XY:

0.0254

AC XY:

1888

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0104

AC:

431

AN:

41524

American (AMR)

AF:

0.0198

AC:

302

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0271

AC:

AN:

3472

East Asian (EAS)

AF:

0.0273

AC:

141

AN:

5170

South Asian (SAS)

AF:

0.0597

AC:

287

AN:

4810

European-Finnish (FIN)

AF:

0.0102

AC:

108

AN:

10606

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0371

AC:

2523

AN:

67974

Other (OTH)

AF:

0.0342

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

192

384

575

767

959

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.0345

Hom.:

304

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

Eigen

Benign

0.0045

Eigen_PC

Benign

0.028

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0030

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

2.4

PrimateAI

Benign

0.19

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.053

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0020

Polyphen

0.021

Vest4

0.36

MPC

0.96

ClinPred

0.030

GERP RS

2.8

Varity_R

0.50

gMVP

0.79

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over