7-150995271-T-C

Position:

chr7-150995271-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000603.5(NOS3):c.227T>C(p.Val76Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,610,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

NOS3
NM_000603.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0130

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07657024).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NOS3	NM_000603.5 linkuse as main transcript	c.227T>C	p.Val76Ala	missense_variant	3/27	ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1 linkuse as main transcript	c.227T>C	p.Val76Ala	missense_variant	2/14		NP_001153583.1
NOS3	NM_001160110.1 linkuse as main transcript	c.227T>C	p.Val76Ala	missense_variant	2/14		NP_001153582.1
NOS3	NM_001160109.2 linkuse as main transcript	c.227T>C	p.Val76Ala	missense_variant	2/14		NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8 linkuse as main transcript	c.227T>C	p.Val76Ala	missense_variant	3/27	1	NM_000603.5	ENSP00000297494	P1	P29474-1
NOS3	ENST00000484524.5 linkuse as main transcript	c.227T>C	p.Val76Ala	missense_variant	2/14	1		ENSP00000420215		P29474-2
NOS3	ENST00000467517.1 linkuse as main transcript	c.227T>C	p.Val76Ala	missense_variant	2/14	1		ENSP00000420551		P29474-3
NOS3	ENST00000461406.5 linkuse as main transcript	c.-80T>C		5_prime_UTR_variant	2/24	2		ENSP00000417143

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000281

AC:

AN:

248708

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135012

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:

0.0000626

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1459104

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

725876

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:

0.0000189

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151780

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74130

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000414

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

Nov 18, 2022

The c.227T>C (p.V76A) alteration is located in exon 3 (coding exon 2) of the NOS3 gene. This alteration results from a T to C substitution at nucleotide position 227, causing the valine (V) at amino acid position 76 to be replaced by an alanine (A). 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

0.065

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.099

T;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.51

T;T;T

M_CAP

Benign

0.0046

MetaRNN

Benign

0.077

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;L

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

0.87

N;N;N

REVEL

Benign

0.059

Sift

Benign

0.37

T;T;T

Sift4G

Benign

0.77

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.28

MutPred

0.20

Loss of ubiquitination at K72 (P = 0.0907);Loss of ubiquitination at K72 (P = 0.0907);Loss of ubiquitination at K72 (P = 0.0907);

MVP

0.43

MPC

0.076

ClinPred

0.069

GERP RS

4.1

Varity_R

0.090

gMVP

0.28

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