chr7-150996417-C-T

Position:

• chr7-150996417-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000603.5(NOS3):​c.284C>T​(p.Thr95Ile) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 17)
• Consequence: NOS3 NM_000603.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28441638).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS3	NM_000603.5	c.284C>T	p.Thr95Ile	missense_variant	4/27	ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1	c.284C>T	p.Thr95Ile	missense_variant	3/14		NP_001153583.1
NOS3	NM_001160110.1	c.284C>T	p.Thr95Ile	missense_variant	3/14		NP_001153582.1
NOS3	NM_001160109.2	c.284C>T	p.Thr95Ile	missense_variant	3/14		NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8	c.284C>T	p.Thr95Ile	missense_variant	4/27	1	NM_000603.5	ENSP00000297494	P1
NOS3	ENST00000484524.5	c.284C>T	p.Thr95Ile	missense_variant	3/14	1		ENSP00000420215
NOS3	ENST00000467517.1	c.284C>T	p.Thr95Ile	missense_variant	3/14	1		ENSP00000420551
NOS3	ENST00000461406.5	c.-37+1103C>T		intron_variant		2		ENSP00000417143

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Essential hypertension Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Aug 14, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.;.
Eigen	Benign	0.053
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.0	M;M;M
MutationTaster	Benign	0.63	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Benign	0.11
Sift	Uncertain	0.012	D;D;D
Sift4G	Uncertain	0.040	D;D;D
Polyphen		0.63	P;.;.
Vest4		0.54
MutPred		0.34		Loss of phosphorylation at T95 (P = 0.0061);Loss of phosphorylation at T95 (P = 0.0061);Loss of phosphorylation at T95 (P = 0.0061);
MVP		0.66
MPC		0.32
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.47
gMVP		0.55

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

Other links and lift over

dbSNP: rs1802424536; hg19: chr7-150693505;