17-27758954-G-C

Variant names:

• chr17-27758954-G-C
• rs1908019475
• NM_000625.4:c.3281C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000625.4(NOS2):​c.3281C>G​(p.Thr1094Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,460,402 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1094I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NOS2 NM_000625.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.67
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS2	NM_000625.4	c.3281C>G	p.Thr1094Ser	missense_variant	Exon 26 of 27	ENST00000313735.11	NP_000616.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS2	ENST00000313735.11	c.3281C>G	p.Thr1094Ser	missense_variant	Exon 26 of 27	1	NM_000625.4	ENSP00000327251.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460402 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726546

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111410

Other (OTH) AF: 0.00 AC: 0 AN: 60338

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.41	T;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.65	T;T;T
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.8	M;.;.
PhyloP100		4.7
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.5	N;.;.
REVEL	Uncertain	0.44
Sift	Benign	0.049	D;.;.
Sift4G	Uncertain	0.053	T;.;T
Polyphen		0.094	B;.;.
Vest4		0.24
MutPred		0.55		Gain of MoRF binding (P = 0.1078);.;.;
MVP		0.81
MPC		0.15
ClinPred		0.84	D
GERP RS		3.5
Varity_R		0.25
gMVP		0.45
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1908019475; hg19: chr17-26085980;