rs79467411

Positions:

• chr7-151003203-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001160111.1(NOS3):​c.1805G>A​(p.Cys602Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0958 in 452,870 control chromosomes in the GnomAD database, including 2,419 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (900 hom., cov: 32)
  • Exomes 𝑓: 0.093 (1519 hom.)
• Consequence: NOS3 NM_001160111.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.911

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013646781).
• BP6: Variant 7-151003203-G-A is Benign according to our data. Variant chr7-151003203-G-A is described in ClinVar as [Benign]. Clinvar id is 403247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS3	NM_000603.5	c.1752+899G>A		intron_variant		ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1	c.1805G>A	p.Cys602Tyr	missense_variant	14/14		NP_001153583.1
NOS3	NM_001160110.1	c.1753-108G>A		intron_variant			NP_001153582.1
NOS3	NM_001160109.2	c.1753-454G>A		intron_variant			NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000484524.5	c.1805G>A	p.Cys602Tyr	missense_variant	14/14	1		ENSP00000420215.1
NOS3	ENST00000297494.8	c.1752+899G>A		intron_variant		1	NM_000603.5	ENSP00000297494.3
NOS3	ENST00000467517.1	c.1753-108G>A		intron_variant		1		ENSP00000420551.1
NOS3	ENST00000461406.5	c.1134+899G>A		intron_variant		2		ENSP00000417143.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15467 AN: 151964 Hom.: 902 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0767

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0881

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0792

Gnomad OTH AF: 0.108

GnomAD3 exomes AF: 0.0915 AC: 11649 AN: 127250 Hom.: 605 AF XY: 0.0956 AC XY: 6657 AN XY: 69634

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.0595

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.0872

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.0946

Gnomad NFE exome AF: 0.0757

Gnomad OTH exome AF: 0.0824

GnomAD4 exome AF: 0.0928 AC: 27920 AN: 300788 Hom.: 1519 Cov.: 0 AF XY: 0.0988 AC XY: 16928 AN XY: 171310

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.0597

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.0915

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.0934

Gnomad4 NFE exome AF: 0.0785

Gnomad4 OTH exome AF: 0.0848

GnomAD4 genome AF: 0.102 AC: 15463 AN: 152082 Hom.: 900 Cov.: 32 AF XY: 0.103 AC XY: 7681 AN XY: 74332

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.0765

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.0881

Gnomad4 SAS AF: 0.142

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.0792

Gnomad4 OTH AF: 0.107

Alfa AF: 0.0935 Hom.: 119

Bravo AF: 0.100

TwinsUK AF: 0.0666 AC: 247

ALSPAC AF: 0.0675 AC: 260

ExAC AF: 0.0994 AC: 1437

Asia WGS AF: 0.124 AC: 431 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

NOS3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 02, 2019

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

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.6
DANN	Benign	0.31
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.048
Sift	Benign	0.12	T
Sift4G	Benign	0.12	T
Vest4		0.051
ClinPred		0.0015	T
GERP RS		-0.79

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: rs79467411; hg19: chr7-150700291; COSMIC: COSV52490113; COSMIC: COSV52490113;