12-117215323-C-T

Position:

chr12-117215323-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_000620.5(NOS1):c.4291G>A(p.Val1431Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000011 in 1,546,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

NOS1
NM_000620.5 missense, splice_region

Scores

Splicing: ADA: 0.9836

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.89

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 -3 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.

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS1	NM_000620.5 linkuse as main transcript	c.4291G>A	p.Val1431Ile	missense_variant, splice_region_variant	29/29	ENST00000317775.11	NP_000611.1	P29475-1B3VK56A0PJJ7B4DG68
NOS1	NM_001204218.2 linkuse as main transcript	c.4393G>A	p.Val1465Ile	missense_variant, splice_region_variant	30/30		NP_001191147.1	P29475-5A0PJJ7B4DG68
NOS1	NM_001204213.2 linkuse as main transcript	c.3283G>A	p.Val1095Ile	missense_variant, splice_region_variant	28/28		NP_001191142.1	P29475-3A0PJJ7B4DG68
NOS1	NM_001204214.2 linkuse as main transcript	c.3283G>A	p.Val1095Ile	missense_variant, splice_region_variant	28/28		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.4291G>A	p.Val1431Ile	missense_variant, splice_region_variant	29/29	1	NM_000620.5	ENSP00000320758.6	P29475-1
NOS1	ENST00000338101.8 linkuse as main transcript	c.4393G>A	p.Val1465Ile	missense_variant, splice_region_variant	29/29	5		ENSP00000337459.4	P29475-5
NOS1	ENST00000618760.4 linkuse as main transcript	c.4393G>A	p.Val1465Ile	missense_variant, splice_region_variant	30/30	5		ENSP00000477999.1	P29475-5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

214072

Hom.:

AF XY:

0.0000427

AC XY:

AN XY:

117060

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000236

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000115

AC:

AN:

1394736

Hom.:

Cov.:

AF XY:

0.0000173

AC XY:

AN XY:

692282

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000212

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000331

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

Apr 05, 2023

The c.4393G>A (p.V1465I) alteration is located in exon 30 (coding exon 29) of the NOS1 gene. This alteration results from a G to A substitution at nucleotide position 4393, causing the valine (V) at amino acid position 1465 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

0.11

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.;.;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.74

T;T;.;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.18

T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.9

M;.;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.42

N;.;N;.

REVEL

Benign

0.20

Sift

Pathogenic

0.0

D;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.59

P;.;.;.

Vest4

0.33

MutPred

0.14

Gain of methylation at K1426 (P = 0.1139);.;.;.;

MVP

0.35

MPC

0.46

ClinPred

0.31

GERP RS

5.0

Varity_R

0.32

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.84

SpliceAI score (max)

0.090

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