rs7792133

chr7-151007158-G-Achr7-151007158-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000603.5(NOS3):c.1994G>A(p.Arg665His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,914 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0051 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (1 hom.)
• Consequence: NOS3 NM_000603.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.86

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007344246).
• BP6: Variant 7-151007158-G-A is Benign according to our data. Variant chr7-151007158-G-A is described in ClinVar as [Benign]. Clinvar id is 776273.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00511 (778/152348) while in subpopulation AFR AF= 0.0177 (734/41572). AF 95% confidence interval is 0.0166. There are 7 homozygotes in gnomad4. There are 361 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 776 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS3	NM_000603.5	c.1994G>A	p.Arg665His	missense_variant	17/27	ENST00000297494.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS3	ENST00000297494.8	c.1994G>A	p.Arg665His	missense_variant	17/27	1	NM_000603.5	P1
NOS3	ENST00000461406.5	c.1376G>A	p.Arg459His	missense_variant	14/24	2

Frequencies

GnomAD3 genomes AF: 0.00510 AC: 776 AN: 152230 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00138 AC: 346 AN: 250894 Hom.: 1 AF XY: 0.000951 AC XY: 129 AN XY: 135692

Gnomad AFR exome AF: 0.0190

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000883

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000614 AC: 898 AN: 1461566 Hom.: 1 Cov.: 33 AF XY: 0.000534 AC XY: 388 AN XY: 727100

Gnomad4 AFR exome AF: 0.0191

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00511 AC: 778 AN: 152348 Hom.: 7 Cov.: 33 AF XY: 0.00485 AC XY: 361 AN XY: 74498

Gnomad4 AFR AF: 0.0177

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.00533

ESP6500AA AF: 0.0184 AC: 81

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00164 AC: 199

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	23
Dann	Benign	0.25
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Benign	0.0073	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.060	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	4.5	N;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;T
Sift4G	Benign	0.94	T;T
Polyphen		0.0010	B;B
Vest4		0.24
MVP		0.80
MPC		0.62
ClinPred		0.018	T
GERP RS		4.9
Varity_R		0.056
gMVP		0.53

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: rs7792133; hg19: chr7-150704246; COSMIC: COSV52493002; COSMIC: COSV52493002;