rs3730017

Variant names:

• chr17-27782076-G-A
• rs3730017
• NM_000625.4:c.661C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000625.4(NOS2):​c.661C>T​(p.Arg221Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0315 in 1,613,922 control chromosomes in the GnomAD database, including 1,995 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.069 (784 hom., cov: 32)
  • Exomes 𝑓: 0.028 (1211 hom.)
• Consequence: NOS2 NM_000625.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028842986).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS2	NM_000625.4	c.661C>T	p.Arg221Trp	missense_variant	Exon 7 of 27	ENST00000313735.11	NP_000616.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS2	ENST00000313735.11	c.661C>T	p.Arg221Trp	missense_variant	Exon 7 of 27	1	NM_000625.4	ENSP00000327251.6

Frequencies

GnomAD3 genomes AF: 0.0693 AC: 10530 AN: 151984 Hom.: 782 Cov.: 32

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0611

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00752

Gnomad SAS AF: 0.0475

Gnomad FIN AF: 0.00567

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.0489

GnomAD3 exomes AF: 0.0373 AC: 9367 AN: 251276 Hom.: 456 AF XY: 0.0335 AC XY: 4554 AN XY: 135814

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.0616

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.00979

Gnomad SAS exome AF: 0.0458

Gnomad FIN exome AF: 0.00541

Gnomad NFE exome AF: 0.0189

Gnomad OTH exome AF: 0.0271

GnomAD4 exome AF: 0.0276 AC: 40358 AN: 1461820 Hom.: 1211 Cov.: 33 AF XY: 0.0274 AC XY: 19956 AN XY: 727200

Gnomad4 AFR exome AF: 0.190

Gnomad4 AMR exome AF: 0.0618

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.00594

Gnomad4 SAS exome AF: 0.0460

Gnomad4 FIN exome AF: 0.00569

Gnomad4 NFE exome AF: 0.0218

Gnomad4 OTH exome AF: 0.0340

GnomAD4 genome AF: 0.0693 AC: 10547 AN: 152102 Hom.: 784 Cov.: 32 AF XY: 0.0678 AC XY: 5041 AN XY: 74346

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.0618

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.00773

Gnomad4 SAS AF: 0.0472

Gnomad4 FIN AF: 0.00567

Gnomad4 NFE AF: 0.0204

Gnomad4 OTH AF: 0.0483

Alfa AF: 0.0290 Hom.: 386

Bravo AF: 0.0784

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0226 AC: 87

ESP6500AA AF: 0.180 AC: 794

ESP6500EA AF: 0.0230 AC: 198

ExAC AF: 0.0398 AC: 4830

Asia WGS AF: 0.0340 AC: 118 AN: 3478

EpiCase AF: 0.0185

EpiControl AF: 0.0199

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.068
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;L
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-4.0	D;.;.
REVEL	Benign	0.089
Sift	Uncertain	0.019	D;.;.
Sift4G	Uncertain	0.022	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.27
MPC		0.98
ClinPred		0.033	T
GERP RS		2.1
Varity_R		0.34
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3730017; hg19: chr17-26109102; COSMIC: COSV58222998;