chr12-117226750-G-A

Position:

chr12-117226750-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_000620.5(NOS1):c.3637C>T(p.His1213Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,461,692 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000022 ( 1 hom. )

Consequence

NOS1
NM_000620.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.00

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 -4 ACMG points.

PP2

Missense variant where missense usually causes diseases, NOS1

BP4

Computational evidence support a benign effect (MetaRNN=0.29839894).

BS2

High AC in GnomAdExome4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NOS1	NM_000620.5 linkuse as main transcript	c.3637C>T	p.His1213Tyr	missense_variant	24/29	ENST00000317775.11
NOS1	NM_001204218.2 linkuse as main transcript	c.3739C>T	p.His1247Tyr	missense_variant	25/30
NOS1	NM_001204213.2 linkuse as main transcript	c.2629C>T	p.His877Tyr	missense_variant	23/28
NOS1	NM_001204214.2 linkuse as main transcript	c.2629C>T	p.His877Tyr	missense_variant	23/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS1	ENST00000317775.11 linkuse as main transcript	c.3637C>T	p.His1213Tyr	missense_variant	24/29	1	NM_000620.5	P1	P29475-1
NOS1	ENST00000338101.8 linkuse as main transcript	c.3739C>T	p.His1247Tyr	missense_variant	24/29	5			P29475-5
NOS1	ENST00000618760.4 linkuse as main transcript	c.3739C>T	p.His1247Tyr	missense_variant	25/30	5			P29475-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000401

AC:

AN:

249414

Hom.:

AF XY:

0.0000665

AC XY:

AN XY:

135314

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:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461692

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727130

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:

0.000359

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Nov 13, 2023

The c.3739C>T (p.H1247Y) alteration is located in exon 25 (coding exon 24) of the NOS1 gene. This alteration results from a C to T substitution at nucleotide position 3739, causing the histidine (H) at amino acid position 1247 to be replaced by a tyrosine (Y). 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

0.12

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.58

D;.;.;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.0098

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;T;.;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.30

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.43

N;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.2

D;.;N;.

REVEL

Uncertain

0.30

Sift

Benign

0.81

T;.;T;.

Sift4G

Benign

0.67

T;T;T;T

Polyphen

0.014

B;.;.;.

Vest4

0.50

MutPred

0.47

Gain of catalytic residue at S1218 (P = 0);.;.;.;

MVP

0.86

MPC

0.77

ClinPred

0.11

GERP RS

4.5

Varity_R

0.30

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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