Genetic Variant NOS1:p.His902His (chr12-117247465-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_000620.5(NOS1):c.2706C>T(p.His902His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,611,784 control chromosomes in the GnomAD database, including 82,302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.30 ( 7477 hom., cov: 30)

Exomes 𝑓: 0.31 ( 74825 hom. )

Consequence

NOS1
NM_000620.5 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.37

Publications

35 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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 12-117247465-G-A is Benign according to our data. Variant chr12-117247465-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060800.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-1.37 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

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
NOS1	NM_000620.5	MANE Select	c.2706C>T	p.His902His	synonymous	Exon 18 of 29	NP_000611.1
NOS1	NM_001204218.2		c.2808C>T	p.His936His	synonymous	Exon 19 of 30	NP_001191147.1
NOS1	NM_001204213.2		c.1698C>T	p.His566His	synonymous	Exon 17 of 28	NP_001191142.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NOS1	ENST00000317775.11	TSL:1 MANE Select	c.2706C>T	p.His902His	synonymous	Exon 18 of 29	ENSP00000320758.6
NOS1	ENST00000338101.8	TSL:5	c.2808C>T	p.His936His	synonymous	Exon 18 of 29	ENSP00000337459.4
NOS1	ENST00000618760.4	TSL:5	c.2808C>T	p.His936His	synonymous	Exon 19 of 30	ENSP00000477999.1

Frequencies

GnomAD3 genomes

AF:

0.296

AC:

44776

AN:

151302

Hom.:

7453

Cov.:

show subpopulations

Gnomad AFR

AF:

0.197

Gnomad AMI

AF:

0.346

Gnomad AMR

AF:

0.483

Gnomad ASJ

AF:

0.343

Gnomad EAS

AF:

0.490

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.236

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.304

Gnomad OTH

AF:

0.329

GnomAD2 exomes

AF:

0.350

AC:

86657

AN:

247758

AF XY:

0.341

show subpopulations

Gnomad AFR exome

AF:

0.193

Gnomad AMR exome

AF:

0.600

Gnomad ASJ exome

AF:

0.332

Gnomad EAS exome

AF:

0.493

Gnomad FIN exome

AF:

0.248

Gnomad NFE exome

AF:

0.305

Gnomad OTH exome

AF:

0.341

GnomAD4 exome

AF:

0.313

AC:

457509

AN:

1460364

Hom.:

74825

Cov.:

AF XY:

0.313

AC XY:

227195

AN XY:

726476

show subpopulations

African (AFR)

AF:

0.194

AC:

6497

AN:

33438

American (AMR)

AF:

0.587

AC:

26107

AN:

44504

Ashkenazi Jewish (ASJ)

AF:

0.334

AC:

8715

AN:

26100

East Asian (EAS)

AF:

0.482

AC:

19073

AN:

39576

South Asian (SAS)

AF:

0.309

AC:

26594

AN:

85940

European-Finnish (FIN)

AF:

0.254

AC:

13571

AN:

53404

Middle Eastern (MID)

AF:

0.332

AC:

1914

AN:

5766

European-Non Finnish (NFE)

AF:

0.302

AC:

335168

AN:

1111294

Other (OTH)

AF:

0.329

AC:

19870

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

15369

30737

46106

61474

76843

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11114

22228

33342

44456

55570

<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:

0.296

AC:

44823

AN:

151420

Hom.:

7477

Cov.:

AF XY:

0.299

AC XY:

22117

AN XY:

73932

show subpopulations

African (AFR)

AF:

0.197

AC:

8130

AN:

41260

American (AMR)

AF:

0.484

AC:

7337

AN:

15162

Ashkenazi Jewish (ASJ)

AF:

0.343

AC:

1186

AN:

3462

East Asian (EAS)

AF:

0.491

AC:

2496

AN:

5088

South Asian (SAS)

AF:

0.297

AC:

1423

AN:

4786

European-Finnish (FIN)

AF:

0.236

AC:

2481

AN:

10500

Middle Eastern (MID)

AF:

0.350

AC:

103

AN:

294

European-Non Finnish (NFE)

AF:

0.304

AC:

20648

AN:

67868

Other (OTH)

AF:

0.337

AC:

706

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1496

2993

4489

5986

7482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

462

924

1386

1848

2310

<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:

0.309

Hom.:

12272

Bravo

AF:

0.311

Asia WGS

AF:

0.407

AC:

1415

AN:

3478

EpiCase

AF:

0.311

EpiControl

AF:

0.307

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NOS1-related disorder

Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.017

(source)

DANN

Benign

0.87

PhyloP100

-1.4

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

Publications

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over