16-69714966-G-C

Variant names:

• chr16-69714966-G-C
• rs1131341
• NM_000903.3:c.415C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000903.3(NQO1):​c.415C>G​(p.Arg139Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R139W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NQO1 NM_000903.3 missense, splice_region
• Scores: Splicing: ADA: 0.04158
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.40
• Publications: 103 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.243054).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NQO1	NM_000903.3	MANE Select	c.415C>G	p.Arg139Gly	missense splice_region	Exon 4 of 6	NP_000894.1	P15559-1
	NQO1	NM_001025433.2		c.415C>G	p.Arg139Gly	missense splice_region	Exon 4 of 5	NP_001020604.1	P15559-2
	NQO1	NM_001025434.2		c.304-1837C>G		intron	N/A	NP_001020605.1	P15559-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NQO1	ENST00000320623.10	TSL:1 MANE Select	c.415C>G	p.Arg139Gly	missense splice_region	Exon 4 of 6	ENSP00000319788.5	P15559-1
	NQO1	ENST00000564043.1	TSL:1	c.352C>G	p.Arg118Gly	missense splice_region	Exon 4 of 6	ENSP00000455020.1	H3BNV2
	NQO1	ENST00000379047.7	TSL:1	c.415C>G	p.Arg139Gly	missense splice_region	Exon 4 of 5	ENSP00000368335.3	P15559-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.74	N
PhyloP100		2.4
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.058
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.46	P
Vest4		0.32
MutPred		0.46		Loss of solvent accessibility (P = 0.0329)
MVP		0.50
MPC		0.61
ClinPred		0.47	T
GERP RS		2.8
Varity_R		0.55
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.042
dbscSNV1_RF	Benign	0.19
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

Other links and lift over

dbSNP: rs1131341; hg19: chr16-69748869;