7-151009552-G-C

Variant names:

• chr7-151009552-G-C
• rs3918232
• NM_000603.5:c.2479G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000603.5(NOS3):​c.2479G>C​(p.Val827Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,391,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V827M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: NOS3 NM_000603.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.51

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16410542).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS3	NM_000603.5	c.2479G>C	p.Val827Leu	missense_variant	Exon 20 of 27	ENST00000297494.8	NP_000594.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8	c.2479G>C	p.Val827Leu	missense_variant	Exon 20 of 27	1	NM_000603.5	ENSP00000297494.3
NOS3	ENST00000461406.5	c.1861G>C	p.Val621Leu	missense_variant	Exon 17 of 24	2		ENSP00000417143.1
NOS3	ENST00000475017.1	c.358G>C	p.Val120Leu	missense_variant	Exon 3 of 7	2		ENSP00000418245.1
NOS3	ENST00000473057.1	n.423G>C		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1391310 Hom.: 0 Cov.: 35 AF XY: 0.00000146 AC XY: 1 AN XY: 685926

Gnomad4 AFR exome AF: 0.0000318

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.12
Sift	Benign	0.27	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.058	B;B
Vest4		0.19
MutPred		0.55		Gain of glycosylation at P826 (P = 0.1266);.;
MVP		0.66
MPC		0.58
ClinPred		0.45	T
GERP RS		-0.10
Varity_R		0.072
gMVP		0.35

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: rs3918232; hg19: chr7-150706640;