Genetic Variant NOS1:c.*8C>T (chr12-117215301-G-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000620.5(NOS1):c.*8C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000485 in 1,557,412 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 2 hom. )

Consequence

NOS1
NM_000620.5 3_prime_UTR

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.05

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 12-117215301-G-A is Benign according to our data. Variant chr12-117215301-G-A is described in ClinVar as [Benign]. Clinvar id is 3033399.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 390 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5 link	c.*8C>T	3_prime_UTR_variant	Exon 29 of 29	ENST00000317775.11	NP_000611.1	P29475-1B3VK56A0PJJ7B4DG68
NOS1	NM_001204218.2 link	c.*8C>T	3_prime_UTR_variant	Exon 30 of 30		NP_001191147.1	P29475-5A0PJJ7B4DG68
NOS1	NM_001204213.2 link	c.*8C>T	3_prime_UTR_variant	Exon 28 of 28		NP_001191142.1	P29475-3A0PJJ7B4DG68
NOS1	NM_001204214.2 link	c.*8C>T	3_prime_UTR_variant	Exon 28 of 28		NP_001191143.1	P29475-3A0PJJ7B4DG68

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOS1	ENST00000317775 link	c.*8C>T	3_prime_UTR_variant	Exon 29 of 29	1	NM_000620.5	ENSP00000320758.6	P29475-1
NOS1	ENST00000338101 link	c.*8C>T	3_prime_UTR_variant	Exon 29 of 29	5		ENSP00000337459.4	P29475-5
NOS1	ENST00000618760 link	c.*8C>T	3_prime_UTR_variant	Exon 30 of 30	5		ENSP00000477999.1	P29475-5

Frequencies

GnomAD3 genomes

AF:

0.00256

AC:

390

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00900

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

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:

0.000955

GnomAD3 exomes

AF:

0.000677

AC:

149

AN:

220178

Hom.:

AF XY:

0.000565

AC XY:

AN XY:

120252

show subpopulations

Gnomad AFR exome

AF:

0.00926

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000198

GnomAD4 exome

AF:

0.000260

AC:

365

AN:

1405088

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

139

AN XY:

697708

show subpopulations

Gnomad4 AFR exome

AF:

0.0103

Gnomad4 AMR exome

AF:

0.000558

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000130

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000554

Gnomad4 OTH exome

AF:

0.000278

GnomAD4 genome

AF:

0.00256

AC:

390

AN:

152324

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

183

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00897

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00170

Hom.:

Bravo

AF:

0.00332

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NOS1-related disorder

Benign:1

Jun 17, 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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over