rs76090928

Positions:

chr12-117330349-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_000620.5(NOS1):c.721G>A(p.Asp241Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00261 in 1,610,320 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 9 hom. )

Consequence

NOS1
NM_000620.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.55

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 -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NOS1. . Gene score misZ 3.6832 (greater than the threshold 3.09). Trascript score misZ 4.7179 (greater than threshold 3.09). GenCC has associacion of gene with idiopathic achalasia.

BP4

Computational evidence support a benign effect (MetaRNN=0.0079512).

BP6

Variant 12-117330349-C-T is Benign according to our data. Variant chr12-117330349-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 790463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 298 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS1	NM_000620.5 linkuse as main transcript	c.721G>A	p.Asp241Asn	missense_variant	2/29	ENST00000317775.11	NP_000611.1	P29475-1B3VK56A0PJJ7B4DG68
NOS1	NM_001204218.2 linkuse as main transcript	c.721G>A	p.Asp241Asn	missense_variant	2/30		NP_001191147.1	P29475-5A0PJJ7B4DG68

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NOS1	ENST00000317775.11 linkuse as main transcript	c.721G>A	p.Asp241Asn	missense_variant	2/29	1	NM_000620.5	ENSP00000320758.6	P29475-1
NOS1	ENST00000338101.8 linkuse as main transcript	c.721G>A	p.Asp241Asn	missense_variant	1/29	5		ENSP00000337459.4	P29475-5
NOS1	ENST00000618760.4 linkuse as main transcript	c.721G>A	p.Asp241Asn	missense_variant	2/30	5		ENSP00000477999.1	P29475-5

Frequencies

GnomAD3 genomes

AF:

0.00196

AC:

298

AN:

151784

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000436

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00499

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00272

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00202

AC:

496

AN:

245606

Hom.:

AF XY:

0.00216

AC XY:

288

AN XY:

133130

show subpopulations

Gnomad AFR exome

AF:

0.000518

Gnomad AMR exome

AF:

0.00306

Gnomad ASJ exome

AF:

0.00513

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000101

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00274

Gnomad OTH exome

AF:

0.00433

GnomAD4 exome

AF:

0.00268

AC:

3909

AN:

1458422

Hom.:

Cov.:

AF XY:

0.00264

AC XY:

1914

AN XY:

725014

show subpopulations

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.00386

Gnomad4 ASJ exome

AF:

0.00507

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000140

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.00309

Gnomad4 OTH exome

AF:

0.00209

GnomAD4 genome

AF:

0.00196

AC:

298

AN:

151898

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.000435

Gnomad4 AMR

AF:

0.00499

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000946

Gnomad4 NFE

AF:

0.00272

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00302

Hom.:

Bravo

AF:

0.00277

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00403

AC:

ExAC

AF:

0.00201

AC:

243

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	NOS1: PP2, BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

NOS1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 2019

This variant is classified as likely 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

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.46

T;.;.;T

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.74

T;T;.;T

M_CAP

Benign

0.0083

MetaRNN

Benign

0.0080

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;L;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.1

N;.;N;.

REVEL

Benign

0.14

Sift

Benign

0.030

D;.;D;.

Sift4G

Uncertain

0.055

T;T;T;T

Polyphen

0.38

B;.;.;.

Vest4

0.30

MVP

0.48

MPC

0.26

ClinPred

0.019

GERP RS

4.7

Varity_R

0.15

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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