chr7-150996516-G-A

Position:

• chr7-150996516-G-A

Variant summary

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

The NM_000603.5(NOS3):​c.383G>A​(p.Arg128Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,606,284 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R128W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 28)
  • Exomes 𝑓: 0.0010 (8 hom.)
• Consequence: NOS3 NM_000603.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.968

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074332952).
• BP6: Variant 7-150996516-G-A is Benign according to our data. Variant chr7-150996516-G-A is described in ClinVar as [Benign]. Clinvar id is 775259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 170 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS3	NM_000603.5	c.383G>A	p.Arg128Gln	missense_variant	4/27	ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1	c.383G>A	p.Arg128Gln	missense_variant	3/14		NP_001153583.1
NOS3	NM_001160110.1	c.383G>A	p.Arg128Gln	missense_variant	3/14		NP_001153582.1
NOS3	NM_001160109.2	c.383G>A	p.Arg128Gln	missense_variant	3/14		NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8	c.383G>A	p.Arg128Gln	missense_variant	4/27	1	NM_000603.5	ENSP00000297494	P1
NOS3	ENST00000484524.5	c.383G>A	p.Arg128Gln	missense_variant	3/14	1		ENSP00000420215
NOS3	ENST00000467517.1	c.383G>A	p.Arg128Gln	missense_variant	3/14	1		ENSP00000420551
NOS3	ENST00000461406.5	c.-37+1202G>A		intron_variant		2		ENSP00000417143

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 170 AN: 147880 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.0000755

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000134

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000666

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000806

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00172 AC: 419 AN: 242936 Hom.: 2 AF XY: 0.00174 AC XY: 230 AN XY: 132522

Gnomad AFR exome AF: 0.0000638

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.000204

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00116

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00201

GnomAD4 exome AF: 0.00101 AC: 1470 AN: 1458302 Hom.: 8 Cov.: 34 AF XY: 0.00105 AC XY: 759 AN XY: 725278

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000898

Gnomad4 ASJ exome AF: 0.000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00131

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.000669

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.00115 AC: 170 AN: 147982 Hom.: 1 Cov.: 28 AF XY: 0.00156 AC XY: 112 AN XY: 72006

Gnomad4 AFR AF: 0.0000752

Gnomad4 AMR AF: 0.000134

Gnomad4 ASJ AF: 0.000290

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000667

Gnomad4 FIN AF: 0.0105

Gnomad4 NFE AF: 0.000807

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000780 Hom.: 0

Bravo AF: 0.000389

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000351 AC: 3

ExAC AF: 0.00162 AC: 195

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.000600

EpiControl AF: 0.000892

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	NOS3: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

NOS3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 01, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T;.;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.61	T;T;T
MetaRNN	Benign	0.0074	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.66	N;N;N
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.77	N;N;N
REVEL	Benign	0.092
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0050	B;.;.
Vest4		0.12
MVP		0.39
MPC		0.073
ClinPred		0.019	T
GERP RS		4.1
Varity_R		0.25
gMVP		0.50

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: rs148359917; hg19: chr7-150693604;