Genetic Variant NOS2:p.Thr919Thr (chr17-27762841-T-C) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_000625.4(NOS2):c.2757A>G(p.Thr919Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 1,560,140 control chromosomes in the GnomAD database, including 318,832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.68 ( 35176 hom., cov: 31)

Exomes 𝑓: 0.63 ( 283656 hom. )

Consequence

NOS2
NM_000625.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -1.61

Variant links:

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]

NOS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 17-27762841-T-C is Benign according to our data. Variant chr17-27762841-T-C is described in ClinVar as [Benign]. Clinvar id is 2687955.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.61 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS2	NM_000625.4 link	c.2757A>G	p.Thr919Thr	synonymous_variant	Exon 22 of 27	ENST00000313735.11	NP_000616.3	P35228-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS2	ENST00000313735.11 link	c.2757A>G	p.Thr919Thr	synonymous_variant	Exon 22 of 27	1	NM_000625.4	ENSP00000327251.6		P35228-1

Frequencies

GnomAD3 genomes

AF:

0.676

AC:

102590

AN:

151828

Hom.:

35121

Cov.:

show subpopulations

Gnomad AFR

AF:

0.773

Gnomad AMI

AF:

0.765

Gnomad AMR

AF:

0.662

Gnomad ASJ

AF:

0.689

Gnomad EAS

AF:

0.690

Gnomad SAS

AF:

0.833

Gnomad FIN

AF:

0.613

Gnomad MID

AF:

0.801

Gnomad NFE

AF:

0.614

Gnomad OTH

AF:

0.688

GnomAD3 exomes

AF:

0.660

AC:

113051

AN:

171212

Hom.:

38014

AF XY:

0.668

AC XY:

60719

AN XY:

90896

show subpopulations

Gnomad AFR exome

AF:

0.778

Gnomad AMR exome

AF:

0.614

Gnomad ASJ exome

AF:

0.683

Gnomad EAS exome

AF:

0.686

Gnomad SAS exome

AF:

0.830

Gnomad FIN exome

AF:

0.599

Gnomad NFE exome

AF:

0.610

Gnomad OTH exome

AF:

0.660

GnomAD4 exome

AF:

0.631

AC:

888475

AN:

1408194

Hom.:

283656

Cov.:

AF XY:

0.637

AC XY:

442799

AN XY:

695626

show subpopulations

Gnomad4 AFR exome

AF:

0.785

Gnomad4 AMR exome

AF:

0.620

Gnomad4 ASJ exome

AF:

0.686

Gnomad4 EAS exome

AF:

0.731

Gnomad4 SAS exome

AF:

0.827

Gnomad4 FIN exome

AF:

0.597

Gnomad4 NFE exome

AF:

0.607

Gnomad4 OTH exome

AF:

0.657

GnomAD4 genome

AF:

0.676

AC:

102706

AN:

151946

Hom.:

35176

Cov.:

AF XY:

0.679

AC XY:

50432

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.773

Gnomad4 AMR

AF:

0.663

Gnomad4 ASJ

AF:

0.689

Gnomad4 EAS

AF:

0.689

Gnomad4 SAS

AF:

0.835

Gnomad4 FIN

AF:

0.613

Gnomad4 NFE

AF:

0.614

Gnomad4 OTH

AF:

0.690

Alfa

AF:

0.636

Hom.:

9452

Bravo

AF:

0.677

Asia WGS

AF:

0.773

AC:

2689

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 87% of patients studied by a panel of primary immunodeficiencies. Number of patients: 83. Only high quality variants are reported. -

NOS2-related disorder

Benign:1

Oct 17, 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

-0.84

CADD

Benign

0.053

DANN

Benign

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over