rs1549758

Positions:

• chr7-150998638-T-A
• chr7-150998638-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NOS3 NM_000603.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS3	NM_000603.5	c.774T>A	p.Asp258Glu	missense_variant	7/27	ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1	c.774T>A	p.Asp258Glu	missense_variant	6/14		NP_001153583.1
NOS3	NM_001160110.1	c.774T>A	p.Asp258Glu	missense_variant	6/14		NP_001153582.1
NOS3	NM_001160109.2	c.774T>A	p.Asp258Glu	missense_variant	6/14		NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8	c.774T>A	p.Asp258Glu	missense_variant	7/27	1	NM_000603.5	ENSP00000297494.3
NOS3	ENST00000484524.5	c.774T>A	p.Asp258Glu	missense_variant	6/14	1		ENSP00000420215.1
NOS3	ENST00000467517.1	c.774T>A	p.Asp258Glu	missense_variant	6/14	1		ENSP00000420551.1
NOS3	ENST00000461406.5	c.156T>A	p.Asp52Glu	missense_variant	4/24	2		ENSP00000417143.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455300 Hom.: 0 Cov.: 72 AF XY: 0.00 AC XY: 0 AN XY: 723478

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	3.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;T;.;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.2	M;.;M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.25	B;P;.;.
Vest4		0.69
MutPred		0.70		Gain of sheet (P = 0.0344);.;Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.34
MPC		0.35
ClinPred		0.99	D
GERP RS		-5.3
Varity_R		0.87
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs1549758; hg19: chr7-150695726;