17-27760058-G-C

Variant names:

• chr17-27760058-G-C
• rs1908064565
• NM_000625.4:c.3131C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000625.4(NOS2):​c.3131C>G​(p.Ala1044Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000701 in 1,426,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. A1044V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NOS2 NM_000625.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.85
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS2	NM_000625.4	c.3131C>G	p.Ala1044Gly	missense_variant	Exon 25 of 27	ENST00000313735.11	NP_000616.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS2	ENST00000313735.11	c.3131C>G	p.Ala1044Gly	missense_variant	Exon 25 of 27	1	NM_000625.4	ENSP00000327251.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1426700 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 708644

African (AFR) AF: 0.00 AC: 0 AN: 31760

American (AMR) AF: 0.00 AC: 0 AN: 38574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24068

East Asian (EAS) AF: 0.00 AC: 0 AN: 37672

South Asian (SAS) AF: 0.00 AC: 0 AN: 81302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096414

Other (OTH) AF: 0.00 AC: 0 AN: 58934

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	-0.087	T
MutationAssessor	Pathogenic	3.1	M;.;.
PhyloP100		6.8
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.9	D;.;.
REVEL	Uncertain	0.57
Sift	Benign	0.11	T;.;.
Sift4G	Benign	0.065	T;.;T
Polyphen		0.56	P;.;.
Vest4		0.53
MutPred		0.83		Loss of MoRF binding (P = 0.1398);.;.;
MVP		0.87
MPC		0.29
ClinPred		0.90	D
GERP RS		2.7
Varity_R		0.44
gMVP		0.77

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: rs1908064565; hg19: chr17-26087084;