chr7-150995269-G-C

Position:

• chr7-150995269-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000603.5(NOS3):​c.225G>C​(p.Glu75Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,459,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000069 (0 hom.)
• Consequence: NOS3 NM_000603.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0730

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21246135).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS3	NM_000603.5	c.225G>C	p.Glu75Asp	missense_variant	3/27	ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1	c.225G>C	p.Glu75Asp	missense_variant	2/14		NP_001153583.1
NOS3	NM_001160110.1	c.225G>C	p.Glu75Asp	missense_variant	2/14		NP_001153582.1
NOS3	NM_001160109.2	c.225G>C	p.Glu75Asp	missense_variant	2/14		NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8	c.225G>C	p.Glu75Asp	missense_variant	3/27	1	NM_000603.5	ENSP00000297494	P1
NOS3	ENST00000484524.5	c.225G>C	p.Glu75Asp	missense_variant	2/14	1		ENSP00000420215
NOS3	ENST00000467517.1	c.225G>C	p.Glu75Asp	missense_variant	2/14	1		ENSP00000420551
NOS3	ENST00000461406.5	c.-82G>C		5_prime_UTR_variant	2/24	2		ENSP00000417143

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459316 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 725950

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: 0.00000900

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

Feb 28, 2023

The c.225G>C (p.E75D) alteration is located in exon 3 (coding exon 2) of the NOS3 gene. This alteration results from a G to C substitution at nucleotide position 225, causing the glutamic acid (E) at amino acid position 75 to be replaced by an aspartic acid (D). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.59	T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;M;M
MutationTaster	Benign	0.56	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.050
Sift	Benign	0.50	T;T;T
Sift4G	Benign	0.59	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.54
MutPred		0.28		Loss of ubiquitination at K72 (P = 0.063);Loss of ubiquitination at K72 (P = 0.063);Loss of ubiquitination at K72 (P = 0.063);
MVP		0.35
MPC		0.093
ClinPred		0.44	T
GERP RS		-0.88
Varity_R		0.28
gMVP		0.48

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: rs1007320995; hg19: chr7-150692357;