Variant 7-150996504-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000603.5(NOS3):c.371T>G(p.Leu124Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,606,142 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., cov: 27)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

NOS3
NM_000603.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.32

Variant links:

Genes affected

NOS3 (HGNC:7876): (nitric oxide synthase 3) Nitric oxide is a reactive free radical which acts as a biologic mediator in several processes, including neurotransmission and antimicrobial and antitumoral activities. Nitric oxide is synthesized from L-arginine by nitric oxide synthases. Variations in this gene are associated with susceptibility to coronary spasm. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Oct 2016]

NOS3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NOS3	NM_000603.5 linkuse as main transcript	c.371T>G	p.Leu124Arg	missense_variant	4/27	ENST00000297494.8
NOS3	NM_001160111.1 linkuse as main transcript	c.371T>G	p.Leu124Arg	missense_variant	3/14
NOS3	NM_001160110.1 linkuse as main transcript	c.371T>G	p.Leu124Arg	missense_variant	3/14
NOS3	NM_001160109.2 linkuse as main transcript	c.371T>G	p.Leu124Arg	missense_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS3	ENST00000297494.8 linkuse as main transcript	c.371T>G	p.Leu124Arg	missense_variant	4/27	1	NM_000603.5	P1	P29474-1
NOS3	ENST00000484524.5 linkuse as main transcript	c.371T>G	p.Leu124Arg	missense_variant	3/14	1			P29474-2
NOS3	ENST00000467517.1 linkuse as main transcript	c.371T>G	p.Leu124Arg	missense_variant	3/14	1			P29474-3
NOS3	ENST00000461406.5 linkuse as main transcript	c.-37+1190T>G		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000542

AC:

AN:

147610

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000177

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:

0.000498

GnomAD3 exomes

AF:

0.00000413

AC:

AN:

242398

Hom.:

AF XY:

0.00000756

AC XY:

AN XY:

132258

show subpopulations

Gnomad AFR exome

AF:

0.0000648

Gnomad AMR exome

AF:

0.00

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:

0.00000891

AC:

AN:

1458532

Hom.:

Cov.:

AF XY:

0.00000965

AC XY:

AN XY:

725382

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00

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:

0.0000829

GnomAD4 genome

AF:

0.0000542

AC:

AN:

147610

Hom.:

Cov.:

AF XY:

0.0000557

AC XY:

AN XY:

71776

show subpopulations

Gnomad4 AFR

AF:

0.000177

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:

0.000498

Bravo

AF:

0.0000718

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 12, 2022

The c.371T>G (p.L124R) alteration is located in exon 4 (coding exon 3) of the NOS3 gene. This alteration results from a T to G substitution at nucleotide position 371, causing the leucine (L) at amino acid position 124 to be replaced by an arginine (R). 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

Uncertain

0.080

BayesDel_noAF

Benign

-0.12

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.27

T;.;.

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.70

D;D;D

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.5

L;L;L

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-4.1

D;D;D

REVEL

Benign

0.26

Sift

Benign

0.034

D;D;D

Sift4G

Benign

0.066

T;T;T

Polyphen

0.74

P;.;.

Vest4

0.60

MutPred

0.74

Gain of MoRF binding (P = 0.0189);Gain of MoRF binding (P = 0.0189);Gain of MoRF binding (P = 0.0189);

MVP

0.71

MPC

0.47

ClinPred

0.87

GERP RS

5.0

Varity_R

0.84

gMVP

0.85

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