12-117220186-G-T

Variant names:

Variant summary

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

The NM_000620.5(NOS1):c.4059C>A(p.Val1353Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,613,938 control chromosomes in the GnomAD database, including 467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.026 ( 132 hom., cov: 32)

Exomes 𝑓: 0.012 ( 335 hom. )

Consequence

NOS1
NM_000620.5 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.143

Publications

12 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=-0.54).

BP6

Variant 12-117220186-G-T is Benign according to our data. Variant chr12-117220186-G-T is described in ClinVar as [Benign]. Clinvar id is 3059998.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-0.143 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5 link	c.4059C>A	p.Val1353Val	synonymous_variant	Exon 27 of 29	ENST00000317775.11	NP_000611.1	P29475-1B3VK56A0PJJ7B4DG68
NOS1	NM_001204218.2 link	c.4161C>A	p.Val1387Val	synonymous_variant	Exon 28 of 30		NP_001191147.1	P29475-5A0PJJ7B4DG68
NOS1	NM_001204213.2 link	c.3051C>A	p.Val1017Val	synonymous_variant	Exon 26 of 28		NP_001191142.1	P29475-3A0PJJ7B4DG68
NOS1	NM_001204214.2 link	c.3051C>A	p.Val1017Val	synonymous_variant	Exon 26 of 28		NP_001191143.1	P29475-3A0PJJ7B4DG68

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOS1	ENST00000317775.11 link	c.4059C>A	p.Val1353Val	synonymous_variant	Exon 27 of 29	1	NM_000620.5	ENSP00000320758.6	P29475-1
NOS1	ENST00000338101.8 link	c.4161C>A	p.Val1387Val	synonymous_variant	Exon 27 of 29	5		ENSP00000337459.4	P29475-5
NOS1	ENST00000618760.4 link	c.4161C>A	p.Val1387Val	synonymous_variant	Exon 28 of 30	5		ENSP00000477999.1	P29475-5

Frequencies

GnomAD3 genomes

AF:

0.0265

AC:

4027

AN:

152204

Hom.:

132

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0690

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0197

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0500

Gnomad SAS

AF:

0.0325

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00563

Gnomad OTH

AF:

0.0253

GnomAD2 exomes

AF:

0.0162

AC:

4048

AN:

249668

AF XY:

0.0163

show subpopulations

Gnomad AFR exome

AF:

0.0678

Gnomad AMR exome

AF:

0.0140

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.0462

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.00602

Gnomad OTH exome

AF:

0.0125

GnomAD4 exome

AF:

0.0119

AC:

17390

AN:

1461616

Hom.:

335

Cov.:

AF XY:

0.0123

AC XY:

8910

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.0696

AC:

2330

AN:

33468

American (AMR)

AF:

0.0146

AC:

654

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000650

AC:

AN:

26136

East Asian (EAS)

AF:

0.0738

AC:

2928

AN:

39696

South Asian (SAS)

AF:

0.0295

AC:

2541

AN:

86238

European-Finnish (FIN)

AF:

0.000207

AC:

AN:

53238

Middle Eastern (MID)

AF:

0.0125

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00723

AC:

8038

AN:

1111970

Other (OTH)

AF:

0.0132

AC:

799

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

846

1691

2537

3382

4228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0265

AC:

4034

AN:

152322

Hom.:

132

Cov.:

AF XY:

0.0264

AC XY:

1963

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0690

AC:

2867

AN:

41580

American (AMR)

AF:

0.0196

AC:

300

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.0501

AC:

259

AN:

5168

South Asian (SAS)

AF:

0.0329

AC:

159

AN:

4832

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00563

AC:

383

AN:

68034

Other (OTH)

AF:

0.0246

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

203

406

609

812

1015

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0110

Hom.:

Bravo

AF:

0.0297

Asia WGS

AF:

0.0380

AC:

130

AN:

3478

EpiCase

AF:

0.00676

EpiControl

AF:

0.00735

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NOS1-related disorder

Benign:1

Jan 03, 2024

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

5.2

(source)

DANN

Benign

0.75

PhyloP100

-0.14

Mutation Taster

=100/0

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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12-117220186-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over