dbSNP rs1802310466: NOS3:p.Ala41Thr (chr7-150993924-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000603.5(NOS3):c.121G>A(p.Ala41Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,427,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A41S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

NOS3
NM_000603.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.22

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10778999).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS3	NM_000603.5 link	c.121G>A	p.Ala41Thr	missense_variant	Exon 2 of 27	ENST00000297494.8	NP_000594.2	P29474-1
NOS3	NM_001160111.1 link	c.121G>A	p.Ala41Thr	missense_variant	Exon 1 of 14		NP_001153583.1	P29474-2
NOS3	NM_001160110.1 link	c.121G>A	p.Ala41Thr	missense_variant	Exon 1 of 14		NP_001153582.1	P29474-3
NOS3	NM_001160109.2 link	c.121G>A	p.Ala41Thr	missense_variant	Exon 1 of 14		NP_001153581.1	P29474A0S0A6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOS3	ENST00000297494.8 link	c.121G>A	p.Ala41Thr	missense_variant	Exon 2 of 27	1	NM_000603.5	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5 link	c.121G>A	p.Ala41Thr	missense_variant	Exon 1 of 14	1		ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1 link	c.121G>A	p.Ala41Thr	missense_variant	Exon 1 of 14	1		ENSP00000420551.1	P29474-3
NOS3	ENST00000461406.5 link	c.-148-1279G>A		intron_variant	Intron 1 of 23	2		ENSP00000417143.1	E7ESA7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1427668

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

707614

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:

9.12e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.098

T;.;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.71

T;T;T

M_CAP

Benign

0.0059

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.4

L;L;L

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.30

N;N;N

REVEL

Benign

0.042

Sift

Benign

0.074

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.095

MutPred

0.18

Gain of glycosylation at A41 (P = 0.0027);Gain of glycosylation at A41 (P = 0.0027);Gain of glycosylation at A41 (P = 0.0027);

MVP

0.34

MPC

0.074

ClinPred

0.049

GERP RS

0.38

Varity_R

0.049

gMVP

0.29

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over