7-150998638-T-C

Position:

• chr7-150998638-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000603.5(NOS3):​c.774T>C​(p.Asp258Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.712 in 1,607,270 control chromosomes in the GnomAD database, including 411,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44840 hom., cov: 33)
  • Exomes 𝑓: 0.71 (366949 hom.)
• Consequence: NOS3 NM_000603.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.51

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 7-150998638-T-C is Benign according to our data. Variant chr7-150998638-T-C is described in ClinVar as [Benign]. Clinvar id is 403248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.875 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS3	NM_000603.5	c.774T>C	p.Asp258Asp	synonymous_variant	7/27	ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1	c.774T>C	p.Asp258Asp	synonymous_variant	6/14		NP_001153583.1
NOS3	NM_001160110.1	c.774T>C	p.Asp258Asp	synonymous_variant	6/14		NP_001153582.1
NOS3	NM_001160109.2	c.774T>C	p.Asp258Asp	synonymous_variant	6/14		NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8	c.774T>C	p.Asp258Asp	synonymous_variant	7/27	1	NM_000603.5	ENSP00000297494.3
NOS3	ENST00000484524.5	c.774T>C	p.Asp258Asp	synonymous_variant	6/14	1		ENSP00000420215.1
NOS3	ENST00000467517.1	c.774T>C	p.Asp258Asp	synonymous_variant	6/14	1		ENSP00000420551.1
NOS3	ENST00000461406.5	c.156T>C	p.Asp52Asp	synonymous_variant	4/24	2		ENSP00000417143.1

Frequencies

GnomAD3 genomes AF: 0.761 AC: 115782 AN: 152070 Hom.: 44777 Cov.: 33

Gnomad AFR AF: 0.883

Gnomad AMI AF: 0.755

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.812

Gnomad EAS AF: 0.819

Gnomad SAS AF: 0.852

Gnomad FIN AF: 0.720

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.749

GnomAD3 exomes AF: 0.759 AC: 177937 AN: 234452 Hom.: 68190 AF XY: 0.756 AC XY: 96880 AN XY: 128148

Gnomad AFR exome AF: 0.889

Gnomad AMR exome AF: 0.821

Gnomad ASJ exome AF: 0.798

Gnomad EAS exome AF: 0.819

Gnomad SAS exome AF: 0.854

Gnomad FIN exome AF: 0.719

Gnomad NFE exome AF: 0.690

Gnomad OTH exome AF: 0.730

GnomAD4 exome AF: 0.707 AC: 1028749 AN: 1455082 Hom.: 366949 Cov.: 72 AF XY: 0.711 AC XY: 514631 AN XY: 723366

Gnomad4 AFR exome AF: 0.889

Gnomad4 AMR exome AF: 0.814

Gnomad4 ASJ exome AF: 0.798

Gnomad4 EAS exome AF: 0.852

Gnomad4 SAS exome AF: 0.853

Gnomad4 FIN exome AF: 0.726

Gnomad4 NFE exome AF: 0.676

Gnomad4 OTH exome AF: 0.731

GnomAD4 genome AF: 0.762 AC: 115904 AN: 152188 Hom.: 44840 Cov.: 33 AF XY: 0.764 AC XY: 56812 AN XY: 74396

Gnomad4 AFR AF: 0.883

Gnomad4 AMR AF: 0.751

Gnomad4 ASJ AF: 0.812

Gnomad4 EAS AF: 0.820

Gnomad4 SAS AF: 0.853

Gnomad4 FIN AF: 0.720

Gnomad4 NFE AF: 0.683

Gnomad4 OTH AF: 0.752

Alfa AF: 0.734 Hom.: 21882

Bravo AF: 0.770

Asia WGS AF: 0.850 AC: 2953 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.58
DANN	Benign	0.37

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: rs1549758; hg19: chr7-150695726; COSMIC: COSV52486190; COSMIC: COSV52486190;