NM_000603.5:c.3295G>C

Variant names:

• chr7-151013763-G-C
• rs773162216
• NM_000603.5:c.3295G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000603.5(NOS3):​c.3295G>C​(p.Glu1099Gln) variant causes a missense 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOS3 NM_000603.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.639

Genes affected

NOS3 (HGNC:7876): (nitric oxide synthase 3) Nitric oxide is a reactive free radical which acts as a biologic mediator in several processes, including neurotransmission and antimicrobial and antitumoral activities. Nitric oxide is synthesized from L-arginine by nitric oxide synthases. Variations in this gene are associated with susceptibility to coronary spasm. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ATG9B (HGNC:21899): (autophagy related 9B) This gene functions in the regulation of autophagy, a lysosomal degradation pathway. This gene also functions as an antisense transcript in the posttranscriptional regulation of the endothelial nitric oxide synthase 3 gene, which has 3' overlap with this gene on the opposite strand. Mutations in this gene and disruption of the autophagy process have been associated with multiple cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32180452).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS3	NM_000603.5	c.3295G>C	p.Glu1099Gln	missense_variant	Exon 26 of 27	ENST00000297494.8	NP_000594.2
ATG9B	NR_073169.1	n.2607C>G		non_coding_transcript_exon_variant	Exon 17 of 18
ATG9B	NR_133652.1	n.3344C>G		non_coding_transcript_exon_variant	Exon 16 of 17
ATG9B	XR_007060009.1	n.3387C>G		non_coding_transcript_exon_variant	Exon 14 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8	c.3295G>C	p.Glu1099Gln	missense_variant	Exon 26 of 27	1	NM_000603.5	ENSP00000297494.3
ATG9B	ENST00000605952.5	n.*493C>G		non_coding_transcript_exon_variant	Exon 16 of 17	1		ENSP00000475737.2
ATG9B	ENST00000605952.5	n.*493C>G		3_prime_UTR_variant	Exon 16 of 17	1		ENSP00000475737.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000413 AC: 1 AN: 241952 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 131892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000922

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.0028	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.71	N;N
REVEL	Benign	0.27
Sift	Benign	0.15	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.051	B;B
Vest4		0.12
MutPred		0.66		Gain of catalytic residue at E1099 (P = 0.0468);.;
MVP		0.86
MPC		0.66
ClinPred		0.22	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs773162216; hg19: chr7-150710851;