17-27760050-G-A

Variant names:

• chr17-27760050-G-A
• rs772991341
• NM_000625.4:c.3139C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000625.4(NOS2):​c.3139C>T​(p.Arg1047Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000084 in 1,548,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1047H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: NOS2 NM_000625.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS2	NM_000625.4	c.3139C>T	p.Arg1047Cys	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.3139C>T	p.Arg1047Cys	missense_variant	Exon 25 of 27	1	NM_000625.4	ENSP00000327251.6

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000152 AC: 3 AN: 197696 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000723

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000215

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000788 AC: 11 AN: 1396276 Hom.: 0 Cov.: 31 AF XY: 0.00000289 AC XY: 2 AN XY: 691828

African (AFR) AF: 0.00 AC: 0 AN: 30308

American (AMR) AF: 0.00 AC: 0 AN: 33564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22604

East Asian (EAS) AF: 0.0000276 AC: 1 AN: 36290

South Asian (SAS) AF: 0.00 AC: 0 AN: 77272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51730

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5502

European-Non Finnish (NFE) AF: 0.00000925 AC: 10 AN: 1081570

Other (OTH) AF: 0.00 AC: 0 AN: 57436

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3139C>T (p.R1047C) alteration is located in exon 25 (coding exon 24) of the NOS2 gene. This alteration results from a C to T substitution at nucleotide position 3139, causing the arginine (R) at amino acid position 1047 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	4.5	H;.;.
PhyloP100		1.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-7.2	D;.;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.92
MutPred		0.92		Loss of MoRF binding (P = 0.0095);.;.;
MVP		0.84
MPC		0.75
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.89
gMVP		0.77
Mutation Taster		=74/26	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: rs772991341; hg19: chr17-26087076;