7-150996501-T-C

Position:

• chr7-150996501-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000603.5(NOS3):​c.368T>C​(p.Leu123Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 27)
• Consequence: NOS3 NM_000603.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS3	NM_000603.5	c.368T>C	p.Leu123Pro	missense_variant	4/27	ENST00000297494.8
NOS3	NM_001160111.1	c.368T>C	p.Leu123Pro	missense_variant	3/14
NOS3	NM_001160110.1	c.368T>C	p.Leu123Pro	missense_variant	3/14
NOS3	NM_001160109.2	c.368T>C	p.Leu123Pro	missense_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS3	ENST00000297494.8	c.368T>C	p.Leu123Pro	missense_variant	4/27	1	NM_000603.5	P1
NOS3	ENST00000484524.5	c.368T>C	p.Leu123Pro	missense_variant	3/14	1
NOS3	ENST00000467517.1	c.368T>C	p.Leu123Pro	missense_variant	3/14	1
NOS3	ENST00000461406.5	c.-37+1187T>C		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The c.368T>C (p.L123P) alteration is located in exon 4 (coding exon 3) of the NOS3 gene. This alteration results from a T to C substitution at nucleotide position 368, causing the leucine (L) at amino acid position 123 to be replaced by a proline (P). 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	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	2.9	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.018	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.82
MutPred		0.80		Gain of glycosylation at L123 (P = 0.0234);Gain of glycosylation at L123 (P = 0.0234);Gain of glycosylation at L123 (P = 0.0234);
MVP		0.80
MPC		0.49
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.94
gMVP		0.94

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.

Other links and lift over

hg19: chr7-150693589;