chr12-117222765-C-T

Position:

chr12-117222765-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_000620.5(NOS1):c.3925G>A(p.Val1309Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,864 control chromosomes in the GnomAD database, including 1 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 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 1 hom. )

Consequence

NOS1
NM_000620.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.04

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 Likely_benign. Variant got -5 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=0.16351256).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS1	NM_000620.5 linkuse as main transcript	c.3925G>A	p.Val1309Ile	missense_variant	26/29	ENST00000317775.11	NP_000611.1	P29475-1B3VK56A0PJJ7B4DG68
NOS1	NM_001204218.2 linkuse as main transcript	c.4027G>A	p.Val1343Ile	missense_variant	27/30		NP_001191147.1	P29475-5A0PJJ7B4DG68
NOS1	NM_001204213.2 linkuse as main transcript	c.2917G>A	p.Val973Ile	missense_variant	25/28		NP_001191142.1	P29475-3A0PJJ7B4DG68
NOS1	NM_001204214.2 linkuse as main transcript	c.2917G>A	p.Val973Ile	missense_variant	25/28		NP_001191143.1	P29475-3A0PJJ7B4DG68

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NOS1	ENST00000317775.11 linkuse as main transcript	c.3925G>A	p.Val1309Ile	missense_variant	26/29	1	NM_000620.5	ENSP00000320758.6	P29475-1
NOS1	ENST00000338101.8 linkuse as main transcript	c.4027G>A	p.Val1343Ile	missense_variant	26/29	5		ENSP00000337459.4	P29475-5
NOS1	ENST00000618760.4 linkuse as main transcript	c.4027G>A	p.Val1343Ile	missense_variant	27/30	5		ENSP00000477999.1	P29475-5

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151878

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000401

AC:

AN:

249530

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135372

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151996

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2024

The c.4027G>A (p.V1343I) alteration is located in exon 27 (coding exon 26) of the NOS1 gene. This alteration results from a G to A substitution at nucleotide position 4027, causing the valine (V) at amino acid position 1343 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;.;.;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D;.;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.0

L;.;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.88

N;.;N;.

REVEL

Uncertain

0.35

Sift

Benign

0.15

T;.;T;.

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.73

P;.;.;.

Vest4

0.15

MutPred

0.46

Gain of catalytic residue at R1311 (P = 0.0646);.;.;.;

MVP

0.59

MPC

0.51

ClinPred

0.099

GERP RS

4.0

Varity_R

0.16

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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