7-150995237-G-A

Position:

• chr7-150995237-G-A

Variant summary

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

The NM_000603.5(NOS3):​c.193G>A​(p.Gly65Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NOS3 NM_000603.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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=0.18244362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS3	NM_000603.5	c.193G>A	p.Gly65Arg	missense_variant	3/27	ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1	c.193G>A	p.Gly65Arg	missense_variant	2/14		NP_001153583.1
NOS3	NM_001160110.1	c.193G>A	p.Gly65Arg	missense_variant	2/14		NP_001153582.1
NOS3	NM_001160109.2	c.193G>A	p.Gly65Arg	missense_variant	2/14		NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8	c.193G>A	p.Gly65Arg	missense_variant	3/27	1	NM_000603.5	ENSP00000297494.3
NOS3	ENST00000484524.5	c.193G>A	p.Gly65Arg	missense_variant	2/14	1		ENSP00000420215.1
NOS3	ENST00000467517.1	c.193G>A	p.Gly65Arg	missense_variant	2/14	1		ENSP00000420551.1
NOS3	ENST00000461406	c.-114G>A		5_prime_UTR_variant	2/24	2		ENSP00000417143.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458878 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725700

Gnomad4 AFR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2024

The c.193G>A (p.G65R) alteration is located in exon 3 (coding exon 2) of the NOS3 gene. This alteration results from a G to A substitution at nucleotide position 193, causing the glycine (G) at amino acid position 65 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Benign	0.85
DEOGEN2	Benign	0.098	T;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.36	N;N;N
REVEL	Benign	0.044
Sift	Benign	0.65	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.017	B;.;.
Vest4		0.40
MutPred		0.26		Loss of glycosylation at K67 (P = 0.0604);Loss of glycosylation at K67 (P = 0.0604);Loss of glycosylation at K67 (P = 0.0604);
MVP		0.54
MPC		0.075
ClinPred		0.52	D
GERP RS		3.2
Varity_R		0.066
gMVP		0.29

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: rs1802346879; hg19: chr7-150692325;