12-117218071-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000620.5(NOS1):c.4264G>C(p.Glu1422Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,614,004 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00083 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

NOS1
NM_000620.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.54

Publications

0 publications found

Variant links:

Genes affected

NOS1 (HGNC:7872): (nitric oxide synthase 1) The protein encoded by this gene belongs to the family of nitric oxide synthases, which synthesize nitric oxide from L-arginine. Nitric oxide is a reactive free radical, which acts as a biologic mediator in several processes, including neurotransmission, and antimicrobial and antitumoral activities. In the brain and peripheral nervous system, nitric oxide displays many properties of a neurotransmitter, and has been implicated in neurotoxicity associated with stroke and neurodegenerative diseases, neural regulation of smooth muscle, including peristalsis, and penile erection. This protein is ubiquitously expressed, with high level of expression in skeletal muscle. Multiple transcript variants that differ in the 5' UTR have been described for this gene but the full-length nature of these transcripts is not known. Additionally, alternatively spliced transcript variants encoding different isoforms (some testis-specific) have been found for this gene.[provided by RefSeq, Feb 2011]

NOS1 Gene-Disease associations (from GenCC):

idiopathic achalasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NOS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.032715768).

BP6

Variant 12-117218071-C-G is Benign according to our data. Variant chr12-117218071-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 730599.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000620.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOS1	NM_000620.5	MANE Select	c.4264G>C	p.Glu1422Gln	missense	Exon 28 of 29	NP_000611.1	P29475-1
NOS1	NM_001204218.2		c.4366G>C	p.Glu1456Gln	missense	Exon 29 of 30	NP_001191147.1	P29475-5
NOS1	NM_001204213.2		c.3256G>C	p.Glu1086Gln	missense	Exon 27 of 28	NP_001191142.1	P29475-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOS1	ENST00000317775.11	TSL:1 MANE Select	c.4264G>C	p.Glu1422Gln	missense	Exon 28 of 29	ENSP00000320758.6	P29475-1
NOS1	ENST00000338101.8	TSL:5	c.4366G>C	p.Glu1456Gln	missense	Exon 28 of 29	ENSP00000337459.4	P29475-5
NOS1	ENST00000618760.4	TSL:5	c.4366G>C	p.Glu1456Gln	missense	Exon 29 of 30	ENSP00000477999.1	P29475-5

Frequencies

GnomAD3 genomes

AF:

0.000835

AC:

127

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00302

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000220

AC:

AN:

249488

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.00303

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000718

AC:

105

AN:

1461724

Hom.:

Cov.:

AF XY:

0.0000646

AC XY:

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.00257

AC:

AN:

33474

American (AMR)

AF:

0.000157

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111884

Other (OTH)

AF:

0.000199

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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

AF:

0.000834

AC:

127

AN:

152280

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00301

AC:

125

AN:

41560

American (AMR)

AF:

0.0000654

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000310

Hom.:

Bravo

AF:

0.000850

ESP6500AA

AF:

0.00225

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000281

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.016

MetaRNN

Benign

0.033

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.6

PhyloP100

7.5

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.1

REVEL

Benign

0.18

Sift

Benign

0.073

Sift4G

Benign

0.23

Polyphen

1.0

Vest4

0.67

MVP

0.63

MPC

1.4

ClinPred

0.049

GERP RS

4.7

Varity_R

0.25

gMVP

0.64

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over