Variant 12-117220227-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000620.5(NOS1):c.4018G>A(p.Val1340Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,460,320 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 1 hom. )

Consequence

NOS1
NM_000620.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.13

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant where missense usually causes diseases, NOS1

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NOS1	NM_000620.5 linkuse as main transcript	c.4018G>A	p.Val1340Met	missense_variant	27/29	ENST00000317775.11
NOS1	NM_001204218.2 linkuse as main transcript	c.4120G>A	p.Val1374Met	missense_variant	28/30
NOS1	NM_001204213.2 linkuse as main transcript	c.3010G>A	p.Val1004Met	missense_variant	26/28
NOS1	NM_001204214.2 linkuse as main transcript	c.3010G>A	p.Val1004Met	missense_variant	26/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS1	ENST00000317775.11 linkuse as main transcript	c.4018G>A	p.Val1340Met	missense_variant	27/29	1	NM_000620.5	P1	P29475-1
NOS1	ENST00000338101.8 linkuse as main transcript	c.4120G>A	p.Val1374Met	missense_variant	27/29	5			P29475-5
NOS1	ENST00000618760.4 linkuse as main transcript	c.4120G>A	p.Val1374Met	missense_variant	28/30	5			P29475-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

248180

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134496

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

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:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460320

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726538

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

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

Oct 06, 2021

The c.4120G>A (p.V1374M) alteration is located in exon 28 (coding exon 27) of the NOS1 gene. This alteration results from a G to A substitution at nucleotide position 4120, causing the valine (V) at amino acid position 1374 to be replaced by a methionine (M). 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

0.24

BayesDel_addAF

Benign

0.0061

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;.;.;D

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

D;D;.;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.56

D;D;D;D

MetaSVM

Uncertain

0.15

MutationAssessor

Pathogenic

3.2

M;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.6

D;.;D;.

REVEL

Pathogenic

0.69

Sift

Uncertain

0.013

D;.;D;.

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

0.94

P;.;.;.

Vest4

0.57

MutPred

0.51

Gain of catalytic residue at L1336 (P = 2e-04);.;.;.;

MVP

0.88

MPC

1.4

ClinPred

0.93

GERP RS

3.5

Varity_R

0.17

gMVP

0.76

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