dbSNP rs3782218: NOS1:c.-420-2217G>A (chr12-117333706-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000620.5(NOS1):c.-420-2217G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 152,146 control chromosomes in the GnomAD database, including 3,051 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.19 ( 3051 hom., cov: 32)

Consequence

NOS1
NM_000620.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.774

Publications

20 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5 link	c.-420-2217G>A		intron_variant	Intron 1 of 28	ENST00000317775.11	NP_000611.1	P29475-1B3VK56A0PJJ7B4DG68
NOS1	NM_001204218.2 link	c.-420-2217G>A		intron_variant	Intron 1 of 29		NP_001191147.1	P29475-5A0PJJ7B4DG68

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOS1	ENST00000317775.11 link	c.-420-2217G>A	intron_variant	Intron 1 of 28	1	NM_000620.5	ENSP00000320758.6	P29475-1
NOS1	ENST00000618760.4 link	c.-420-2217G>A	intron_variant	Intron 1 of 29	5		ENSP00000477999.1	P29475-5
NOS1	ENST00000549189.1 link	n.471-2217G>A	intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.190

AC:

28950

AN:

152028

Hom.:

3049

Cov.:

show subpopulations

Gnomad AFR

AF:

0.266

Gnomad AMI

AF:

0.0813

Gnomad AMR

AF:

0.120

Gnomad ASJ

AF:

0.203

Gnomad EAS

AF:

0.0390

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.173

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.182

Gnomad OTH

AF:

0.178

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.190

AC:

28970

AN:

152146

Hom.:

3051

Cov.:

AF XY:

0.186

AC XY:

13857

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.266

AC:

11018

AN:

41482

American (AMR)

AF:

0.120

AC:

1831

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.203

AC:

705

AN:

3468

East Asian (EAS)

AF:

0.0390

AC:

202

AN:

5174

South Asian (SAS)

AF:

0.112

AC:

537

AN:

4816

European-Finnish (FIN)

AF:

0.173

AC:

1831

AN:

10584

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.182

AC:

12345

AN:

68002

Other (OTH)

AF:

0.177

AC:

374

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1188

2375

3563

4750

5938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

306

612

918

1224

1530

<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:

0.187

Hom.:

4929

Bravo

AF:

0.192

Asia WGS

AF:

0.0870

AC:

303

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.3

(source)

DANN

Benign

0.79

PhyloP100

0.77

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over