7-151007162-C-G

Variant names:

• chr7-151007162-C-G
• rs2566514
• NM_000603.5:c.1998C>G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000603.5(NOS3):​c.1998C>G​(p.Ala666Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,613,552 control chromosomes in the GnomAD database, including 72,128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10911 hom., cov: 33)
  • Exomes 𝑓: 0.28 (61217 hom.)
• Consequence: NOS3 NM_000603.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.57

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 7-151007162-C-G is Benign according to our data. Variant chr7-151007162-C-G is described in ClinVar as [Benign]. Clinvar id is 403249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS3	NM_000603.5	c.1998C>G	p.Ala666Ala	synonymous_variant	Exon 17 of 27	ENST00000297494.8	NP_000594.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8	c.1998C>G	p.Ala666Ala	synonymous_variant	Exon 17 of 27	1	NM_000603.5	ENSP00000297494.3
NOS3	ENST00000461406.5	c.1380C>G	p.Ala460Ala	synonymous_variant	Exon 14 of 24	2		ENSP00000417143.1

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54276 AN: 151992 Hom.: 10867 Cov.: 33

Gnomad AFR AF: 0.503

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.338

GnomAD3 exomes AF: 0.345 AC: 86546 AN: 250728 Hom.: 17018 AF XY: 0.330 AC XY: 44801 AN XY: 135618

Gnomad AFR exome AF: 0.511

Gnomad AMR exome AF: 0.587

Gnomad ASJ exome AF: 0.234

Gnomad EAS exome AF: 0.359

Gnomad SAS exome AF: 0.355

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.254

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.276 AC: 403907 AN: 1461442 Hom.: 61217 Cov.: 40 AF XY: 0.277 AC XY: 201252 AN XY: 727040

Gnomad4 AFR exome AF: 0.510

Gnomad4 AMR exome AF: 0.575

Gnomad4 ASJ exome AF: 0.231

Gnomad4 EAS exome AF: 0.409

Gnomad4 SAS exome AF: 0.347

Gnomad4 FIN exome AF: 0.343

Gnomad4 NFE exome AF: 0.245

Gnomad4 OTH exome AF: 0.284

GnomAD4 genome AF: 0.357 AC: 54376 AN: 152110 Hom.: 10911 Cov.: 33 AF XY: 0.363 AC XY: 26992 AN XY: 74346

Gnomad4 AFR AF: 0.503

Gnomad4 AMR AF: 0.457

Gnomad4 ASJ AF: 0.239

Gnomad4 EAS AF: 0.371

Gnomad4 SAS AF: 0.364

Gnomad4 FIN AF: 0.351

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.335

Alfa AF: 0.233 Hom.: 1346

Bravo AF: 0.376

Asia WGS AF: 0.378 AC: 1312 AN: 3478

EpiCase AF: 0.246

EpiControl AF: 0.244

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.1
DANN	Benign	0.74

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: rs2566514; hg19: chr7-150704250; COSMIC: COSV52488879; COSMIC: COSV52488879;