rs3729508

Variant names:

• chr17-27782004-T-C
• rs3729508
• NM_000625.4:c.722+11A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000625.4(NOS2):​c.722+11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 1,611,480 control chromosomes in the GnomAD database, including 307,006 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.67 (34483 hom., cov: 32)
  • Exomes 𝑓: 0.61 (272523 hom.)
• Consequence: NOS2 NM_000625.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.16
• Publications: 50 publications found

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 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-27782004-T-C is Benign according to our data. Variant chr17-27782004-T-C is described in ClinVar as Benign. ClinVar VariationId is 2687961.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS2	NM_000625.4	c.722+11A>G		intron_variant	Intron 7 of 26	ENST00000313735.11	NP_000616.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS2	ENST00000313735.11	c.722+11A>G		intron_variant	Intron 7 of 26	1	NM_000625.4	ENSP00000327251.6

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101331 AN: 151932 Hom.: 34425 Cov.: 32

Gnomad AFR AF: 0.799

Gnomad AMI AF: 0.748

Gnomad AMR AF: 0.688

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.740

Gnomad FIN AF: 0.602

Gnomad MID AF: 0.736

Gnomad NFE AF: 0.598

Gnomad OTH AF: 0.659

GnomAD2 exomes AF: 0.640 AC: 160086 AN: 250122 AF XY: 0.640

Gnomad AFR exome AF: 0.804

Gnomad AMR exome AF: 0.713

Gnomad ASJ exome AF: 0.648

Gnomad EAS exome AF: 0.525

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.595

Gnomad OTH exome AF: 0.639

GnomAD4 exome AF: 0.608 AC: 887227 AN: 1459430 Hom.: 272523 Cov.: 33 AF XY: 0.611 AC XY: 443554 AN XY: 726084

African (AFR) AF: 0.812 AC: 27139 AN: 33420

American (AMR) AF: 0.709 AC: 31663 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 17013 AN: 26110

East Asian (EAS) AF: 0.506 AC: 20069 AN: 39680

South Asian (SAS) AF: 0.730 AC: 62850 AN: 86088

European-Finnish (FIN) AF: 0.599 AC: 31993 AN: 53382

Middle Eastern (MID) AF: 0.734 AC: 4228 AN: 5758

European-Non Finnish (NFE) AF: 0.590 AC: 654656 AN: 1110032

Other (OTH) AF: 0.624 AC: 37616 AN: 60326

GnomAD4 genome AF: 0.667 AC: 101451 AN: 152050 Hom.: 34483 Cov.: 32 AF XY: 0.670 AC XY: 49813 AN XY: 74328

African (AFR) AF: 0.800 AC: 33178 AN: 41494

American (AMR) AF: 0.689 AC: 10522 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 2257 AN: 3472

East Asian (EAS) AF: 0.510 AC: 2632 AN: 5160

South Asian (SAS) AF: 0.741 AC: 3568 AN: 4816

European-Finnish (FIN) AF: 0.602 AC: 6351 AN: 10552

Middle Eastern (MID) AF: 0.740 AC: 216 AN: 292

European-Non Finnish (NFE) AF: 0.598 AC: 40651 AN: 67960

Other (OTH) AF: 0.660 AC: 1395 AN: 2114

Alfa AF: 0.618 Hom.: 52683

Bravo AF: 0.677

Asia WGS AF: 0.629 AC: 2191 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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 86% of patients studied by a panel of primary immunodeficiencies. Number of patients: 82. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.93
DANN	Benign	0.43
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3729508; hg19: chr17-26109030;