Genetic Variant NOS3:p.Asp258Glu (chr7-150998638-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000603.5(NOS3):c.774T>A(p.Asp258Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D258D) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NOS3
NM_000603.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.51

Publications

67 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.76

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000603.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOS3	NM_000603.5	MANE Select	c.774T>A	p.Asp258Glu	missense	Exon 7 of 27	NP_000594.2
NOS3	NM_001160111.1		c.774T>A	p.Asp258Glu	missense	Exon 6 of 14	NP_001153583.1	P29474-2
NOS3	NM_001160110.1		c.774T>A	p.Asp258Glu	missense	Exon 6 of 14	NP_001153582.1	P29474-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NOS3	ENST00000297494.8	TSL:1 MANE Select	c.774T>A	p.Asp258Glu	missense	Exon 7 of 27	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5	TSL:1	c.774T>A	p.Asp258Glu	missense	Exon 6 of 14	ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1	TSL:1	c.774T>A	p.Asp258Glu	missense	Exon 6 of 14	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1455300

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723478

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

43976

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25964

East Asian (EAS)

AF:

0.00

AC:

AN:

39528

South Asian (SAS)

AF:

0.00

AC:

AN:

85410

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50986

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110124

Other (OTH)

AF:

0.00

AC:

AN:

60102

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

3.2

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.086

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.2

PhyloP100

-1.5

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.25

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

0.25

Vest4

0.69

MutPred

0.70

Gain of sheet (P = 0.0344)

MVP

0.34

MPC

0.35

ClinPred

0.99

GERP RS

-5.3

Varity_R

0.87

gMVP

0.61

Mutation Taster

=64/36

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over