7-150996404-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000603.5(NOS3):c.271G>A(p.Asp91Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000312 in 1,378,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., cov: 14)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

NOS3
NM_000603.5 missense, splice_region

Scores

Splicing: ADA: 0.7447

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18464082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NOS3	NM_000603.5 linkuse as main transcript	c.271G>A	p.Asp91Asn	missense_variant, splice_region_variant	4/27	ENST00000297494.8
NOS3	NM_001160111.1 linkuse as main transcript	c.271G>A	p.Asp91Asn	missense_variant, splice_region_variant	3/14
NOS3	NM_001160110.1 linkuse as main transcript	c.271G>A	p.Asp91Asn	missense_variant, splice_region_variant	3/14
NOS3	NM_001160109.2 linkuse as main transcript	c.271G>A	p.Asp91Asn	missense_variant, splice_region_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS3	ENST00000297494.8 linkuse as main transcript	c.271G>A	p.Asp91Asn	missense_variant, splice_region_variant	4/27	1	NM_000603.5	P1	P29474-1
NOS3	ENST00000484524.5 linkuse as main transcript	c.271G>A	p.Asp91Asn	missense_variant, splice_region_variant	3/14	1			P29474-2
NOS3	ENST00000467517.1 linkuse as main transcript	c.271G>A	p.Asp91Asn	missense_variant, splice_region_variant	3/14	1			P29474-3
NOS3	ENST00000461406.5 linkuse as main transcript	c.-37+1090G>A		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000906

AC:

AN:

110418

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000726

GnomAD3 exomes

AF:

0.0000129

AC:

AN:

155154

Hom.:

AF XY:

0.00

AC XY:

AN XY:

82750

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000341

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000331

AC:

AN:

1268234

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

624354

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000372

Gnomad4 OTH exome

AF:

0.000102

GnomAD4 genome

AF:

0.00000906

AC:

AN:

110418

Hom.:

Cov.:

AF XY:

0.0000191

AC XY:

AN XY:

52360

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000726

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000302

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 26, 2022

The c.271G>A (p.D91N) alteration is located in exon 4 (coding exon 3) of the NOS3 gene. This alteration results from a G to A substitution at nucleotide position 271, causing the aspartic acid (D) at amino acid position 91 to be replaced by an asparagine (N). 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

0.10

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.68

Cadd

Uncertain

Dann

Uncertain

0.98

DEOGEN2

Benign

0.10

T;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

0.017

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.0097

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;L

MutationTaster

Benign

0.97

D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.19

N;N;N

REVEL

Benign

0.069

Sift

Benign

0.62

T;T;T

Sift4G

Benign

0.49

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.32

MVP

0.62

MPC

0.080

ClinPred

0.11

GERP RS

4.9

Varity_R

0.27

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.74

dbscSNV1_RF

Benign

0.55

SpliceAI score (max)

0.11

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