rs1131341

chr16-69714966-G-Achr16-69714966-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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

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 -8 ACMG points.

• 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/exons	MANE	UniProt
NQO1	NM_000903.3	c.415C>T	p.Arg139Trp	missense_variant, splice_region_variant	4/6	ENST00000320623.10
NQO1	NM_001025433.2	c.415C>T	p.Arg139Trp	missense_variant, splice_region_variant	4/5
NQO1	NM_001025434.2	c.304-1837C>T		intron_variant
NQO1	NM_001286137.2	c.303+3157C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NQO1	ENST00000320623.10	c.415C>T	p.Arg139Trp	missense_variant, splice_region_variant	4/6	1	NM_000903.3	P1

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 3951 AN: 152036 Hom.: 71 Cov.: 32

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

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.: 29 AF XY: 0.0401 AC XY: 29079 AN XY: 725016

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.: 73 Cov.: 32 AF XY: 0.0254 AC XY: 1888 AN XY: 74388

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: 54

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	T
BayesDel_noAF	Benign	-0.51
Cadd	Uncertain	26
Dann	Pathogenic	1.0
Eigen	Benign	0.0045
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;D;D
MetaRNN	Benign	0.0030	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	1.0	D;D;D;N;N;N
PrimateAI	Benign	0.19	T
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	T
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

Other links and lift over

dbSNP: rs1131341; hg19: chr16-69748869; COSMIC: COSV57731384; COSMIC: COSV57731384;