7-150995229-C-T

Variant names:

• chr7-150995229-C-T
• NM_000603.5:c.185C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000603.5(NOS3):​c.185C>T​(p.Pro62Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NOS3 NM_000603.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.70

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26174396).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS3	NM_000603.5	c.185C>T	p.Pro62Leu	missense_variant	Exon 3 of 27	ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1	c.185C>T	p.Pro62Leu	missense_variant	Exon 2 of 14		NP_001153583.1
NOS3	NM_001160110.1	c.185C>T	p.Pro62Leu	missense_variant	Exon 2 of 14		NP_001153582.1
NOS3	NM_001160109.2	c.185C>T	p.Pro62Leu	missense_variant	Exon 2 of 14		NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8	c.185C>T	p.Pro62Leu	missense_variant	Exon 3 of 27	1	NM_000603.5	ENSP00000297494.3
NOS3	ENST00000484524.5	c.185C>T	p.Pro62Leu	missense_variant	Exon 2 of 14	1		ENSP00000420215.1
NOS3	ENST00000467517.1	c.185C>T	p.Pro62Leu	missense_variant	Exon 2 of 14	1		ENSP00000420551.1
NOS3	ENST00000461406	c.-122C>T		5_prime_UTR_variant	Exon 2 of 24	2		ENSP00000417143.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458632 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725616

Gnomad4 AFR exome AF: 0.0000598

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.185C>T (p.P62L) alteration is located in exon 3 (coding exon 2) of the NOS3 gene. This alteration results from a C to T substitution at nucleotide position 185, causing the proline (P) at amino acid position 62 to be replaced by a leucine (L). 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	Benign	0.078
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.051
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.029	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.35
MutPred		0.24		Loss of glycosylation at P63 (P = 0.0535);Loss of glycosylation at P63 (P = 0.0535);Loss of glycosylation at P63 (P = 0.0535);
MVP		0.68
MPC		0.099
ClinPred		0.74	D
GERP RS		4.2
Varity_R		0.095
gMVP		0.30

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: chr7-150692317;