chr7-150995225-C-G

Position:

• chr7-150995225-C-G

Variant summary

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

The NM_000603.5(NOS3):​c.181C>G​(p.Gln61Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NOS3 NM_000603.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18

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=0.07056129).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS3	NM_000603.5	c.181C>G	p.Gln61Glu	missense_variant	3/27	ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1	c.181C>G	p.Gln61Glu	missense_variant	2/14		NP_001153583.1
NOS3	NM_001160110.1	c.181C>G	p.Gln61Glu	missense_variant	2/14		NP_001153582.1
NOS3	NM_001160109.2	c.181C>G	p.Gln61Glu	missense_variant	2/14		NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8	c.181C>G	p.Gln61Glu	missense_variant	3/27	1	NM_000603.5	ENSP00000297494.3
NOS3	ENST00000484524.5	c.181C>G	p.Gln61Glu	missense_variant	2/14	1		ENSP00000420215.1
NOS3	ENST00000467517.1	c.181C>G	p.Gln61Glu	missense_variant	2/14	1		ENSP00000420551.1
NOS3	ENST00000461406	c.-126C>G		5_prime_UTR_variant	2/24	2		ENSP00000417143.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457784 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725176

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: 9.01e-7

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2024

The c.181C>G (p.Q61E) alteration is located in exon 3 (coding exon 2) of the NOS3 gene. This alteration results from a C to G substitution at nucleotide position 181, causing the glutamine (Q) at amino acid position 61 to be replaced by a glutamic acid (E). 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	0.096
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Benign	0.21
DEOGEN2	Benign	0.14	T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.071	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.18	N;N;N
REVEL	Benign	0.033
Sift	Benign	0.52	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0030	B;.;.
Vest4		0.18
MutPred		0.20		Gain of solvent accessibility (P = 0.0421);Gain of solvent accessibility (P = 0.0421);Gain of solvent accessibility (P = 0.0421);
MVP		0.31
MPC		0.069
ClinPred		0.034	T
GERP RS		1.2
Varity_R		0.060
gMVP		0.12

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: chr7-150692313;