rs1137933

chr17-27778906-G-Achr17-27778906-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000625.4(NOS2):c.1155C>T(p.Asp385=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,606,554 control chromosomes in the GnomAD database, including 38,212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3380 hom., cov: 31)
  • Exomes 𝑓: 0.22 (34832 hom.)
• Consequence: NOS2 NM_000625.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.631

Genes affected

NOS2 (HGNC:7873): (nitric oxide synthase 2) Nitric oxide is a reactive free radical which acts as a biologic mediator in several processes, including neurotransmission and antimicrobial and antitumoral activities. This gene encodes a nitric oxide synthase which is expressed in liver and is inducible by a combination of lipopolysaccharide and certain cytokines. Three related pseudogenes are located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 17-27778906-G-A is Benign according to our data. Variant chr17-27778906-G-A is described in ClinVar as [Benign]. Clinvar id is 2688251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.631 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS2	NM_000625.4	c.1155C>T	p.Asp385=	synonymous_variant	10/27	ENST00000313735.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS2	ENST00000313735.11	c.1155C>T	p.Asp385=	synonymous_variant	10/27	1	NM_000625.4	P2

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31426 AN: 151852 Hom.: 3380 Cov.: 31

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.227

GnomAD3 exomes AF: 0.205 AC: 50930 AN: 248726 Hom.: 5521 AF XY: 0.209 AC XY: 28148 AN XY: 134414

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.168

Gnomad SAS exome AF: 0.194

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.216 AC: 314117 AN: 1454584 Hom.: 34832 Cov.: 34 AF XY: 0.216 AC XY: 156003 AN XY: 722268

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.145

Gnomad4 ASJ exome AF: 0.272

Gnomad4 EAS exome AF: 0.117

Gnomad4 SAS exome AF: 0.192

Gnomad4 FIN exome AF: 0.208

Gnomad4 NFE exome AF: 0.224

Gnomad4 OTH exome AF: 0.212

GnomAD4 genome AF: 0.207 AC: 31432 AN: 151970 Hom.: 3380 Cov.: 31 AF XY: 0.207 AC XY: 15353 AN XY: 74260

Gnomad4 AFR AF: 0.179

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.273

Gnomad4 EAS AF: 0.166

Gnomad4 SAS AF: 0.188

Gnomad4 FIN AF: 0.216

Gnomad4 NFE AF: 0.224

Gnomad4 OTH AF: 0.224

Alfa AF: 0.197 Hom.: 1597

Bravo AF: 0.206

Asia WGS AF: 0.152 AC: 527 AN: 3478

EpiCase AF: 0.231

EpiControl AF: 0.225

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 29% of patients studied by a panel of primary immunodeficiencies. Number of patients: 28. Only high quality variants are reported. -

NOS2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 22, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	2.9
Dann	Benign	0.35

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: rs1137933; hg19: chr17-26105932; COSMIC: COSV58222552;