17-27778906-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000625.4(NOS2):c.1155C>A(p.Asp385Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D385D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NOS2 NM_000625.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS2	NM_000625.4	c.1155C>A	p.Asp385Glu	missense_variant	10/27	ENST00000313735.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS2	ENST00000313735.11	c.1155C>A	p.Asp385Glu	missense_variant	10/27	1	NM_000625.4	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
Cadd	Benign	12
Dann	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	-0.091	T
MutationAssessor	Pathogenic	3.1	M;.;.
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	D;.;.
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0030	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.95
MutPred		0.86		Gain of helix (P = 0.2059);.;.;
MVP		0.38
MPC		1.2
ClinPred		0.99	D
GERP RS		-8.7
Varity_R		0.89
gMVP		0.91

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;