Genetic Variant NOS1:c.-420-12237C>T (chr12-117343726-G-A) – 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.-420-12237C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 152,064 control chromosomes in the GnomAD database, including 10,517 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 0.37 ( 10517 hom., cov: 33)

Consequence

NOS1
NM_000620.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0560

Publications

8 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=-0.84).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5 link	c.-420-12237C>T		intron_variant	Intron 1 of 28	ENST00000317775.11	NP_000611.1	P29475-1B3VK56A0PJJ7B4DG68
NOS1	NM_001204218.2 link	c.-420-12237C>T		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.-420-12237C>T	intron_variant	Intron 1 of 28	1	NM_000620.5	ENSP00000320758.6	P29475-1
NOS1	ENST00000618760.4 link	c.-420-12237C>T	intron_variant	Intron 1 of 29	5		ENSP00000477999.1	P29475-5
NOS1	ENST00000549189.1 link	n.471-12237C>T	intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.368

AC:

55877

AN:

151946

Hom.:

10505

Cov.:

show subpopulations

Gnomad AFR

AF:

0.334

Gnomad AMI

AF:

0.598

Gnomad AMR

AF:

0.402

Gnomad ASJ

AF:

0.422

Gnomad EAS

AF:

0.261

Gnomad SAS

AF:

0.363

Gnomad FIN

AF:

0.376

Gnomad MID

AF:

0.443

Gnomad NFE

AF:

0.381

Gnomad OTH

AF:

0.391

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

GnomAD4 genome

AF:

0.368

AC:

55917

AN:

152064

Hom.:

10517

Cov.:

AF XY:

0.367

AC XY:

27312

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.334

AC:

13859

AN:

41480

American (AMR)

AF:

0.403

AC:

6167

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.422

AC:

1462

AN:

3462

East Asian (EAS)

AF:

0.261

AC:

1348

AN:

5170

South Asian (SAS)

AF:

0.364

AC:

1754

AN:

4822

European-Finnish (FIN)

AF:

0.376

AC:

3972

AN:

10562

Middle Eastern (MID)

AF:

0.446

AC:

131

AN:

294

European-Non Finnish (NFE)

AF:

0.380

AC:

25863

AN:

67972

Other (OTH)

AF:

0.388

AC:

817

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1794

3589

5383

7178

8972

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

544

1088

1632

2176

2720

<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:

0.378

Hom.:

30406

Bravo

AF:

0.369

Asia WGS

AF:

0.307

AC:

1069

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.8

(source)

DANN

Benign

0.66

PhyloP100

-0.056

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