Genetic Variant NOS2:p.Ala1040Glu (chr17-27760070-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000625.4(NOS2):c.3119C>A(p.Ala1040Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A1040V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NOS2
NM_000625.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.821

Publications

0 publications found

Variant links:

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)

NOS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06809762).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000625.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS2	NM_000625.4	MANE Select	c.3119C>A	p.Ala1040Glu	missense	Exon 25 of 27	NP_000616.3	P35228-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOS2	ENST00000313735.11	TSL:1 MANE Select	c.3119C>A	p.Ala1040Glu	missense	Exon 25 of 27	ENSP00000327251.6	P35228-1
NOS2	ENST00000886820.1		c.3119C>A	p.Ala1040Glu	missense	Exon 25 of 27	ENSP00000556879.1
NOS2	ENST00000646938.1		c.3116C>A	p.Ala1039Glu	missense	Exon 24 of 26	ENSP00000494870.1	A0A2R8YDS4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442002

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716972

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32430

American (AMR)

AF:

0.00

AC:

AN:

41172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25062

East Asian (EAS)

AF:

0.00

AC:

AN:

38414

South Asian (SAS)

AF:

0.00

AC:

AN:

83572

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52728

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103414

Other (OTH)

AF:

0.00

AC:

AN:

59552

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Benign

-0.37

CADD

Benign

1.7

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.19

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.34

M_CAP

Benign

0.055

MetaRNN

Benign

0.068

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-1.3

PhyloP100

0.82

PrimateAI

Benign

0.20

PROVEAN

Benign

2.8

REVEL

Benign

0.17

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.17

MutPred

0.52

Gain of catalytic residue at A1040 (P = 0.0452)

MVP

0.41

MPC

0.18

ClinPred

0.088

GERP RS

-0.35

Varity_R

0.051

gMVP

0.48

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over