16-69710994-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000903.3(NQO1):c.807G>C(p.Gln269His) variant causes a missense change. The variant allele was found at a frequency of 0.000903 in 1,612,638 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (6 hom.)
• Consequence: NQO1 NM_000903.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.63

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006585449).
• BP6: Variant 16-69710994-C-G is Benign according to our data. Variant chr16-69710994-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 780185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NQO1	NM_000903.3	c.807G>C	p.Gln269His	missense_variant	6/6	ENST00000320623.10
NQO1	NM_001025433.2	c.705G>C	p.Gln235His	missense_variant	5/5
NQO1	NM_001025434.2	c.693G>C	p.Gln231His	missense_variant	5/5
NQO1	NM_001286137.2	c.591G>C	p.Gln197His	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NQO1	ENST00000320623.10	c.807G>C	p.Gln269His	missense_variant	6/6	1	NM_000903.3	P1

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 586 AN: 152186 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00107 AC: 269 AN: 250676 Hom.: 2 AF XY: 0.000841 AC XY: 114 AN XY: 135506

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.000816

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000596 AC: 871 AN: 1460334 Hom.: 6 Cov.: 31 AF XY: 0.000540 AC XY: 392 AN XY: 726376

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.000901

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000292

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00384 AC: 585 AN: 152304 Hom.: 4 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74474

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000653 Hom.: 1

Bravo AF: 0.00448

ESP6500AA AF: 0.0123 AC: 54

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00139 AC: 169

EpiCase AF: 0.000273

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
MetaRNN	Benign	0.0066	T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.0	N;N;N;N;N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;D;.
Vest4		0.60
MutPred		0.069		.;Loss of helix (P = 0.0626);.;.;.;
MVP		0.70
MPC		1.1
ClinPred		0.030	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs34447156; hg19: chr16-69744897;