chr7-151009552-G-A

Variant names:

• chr7-151009552-G-A
• rs3918232
• NM_000603.5:c.2479G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000603.5(NOS3):​c.2479G>A​(p.Val827Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,543,576 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0046 (17 hom.)
• Consequence: NOS3 NM_000603.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.51
• Publications: 16 publications found

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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065574944).
• BP6: Variant 7-151009552-G-A is Benign according to our data. Variant chr7-151009552-G-A is described in ClinVar as Benign. ClinVar VariationId is 2658167.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 503 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000603.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS3	NM_000603.5	MANE Select	c.2479G>A	p.Val827Met	missense	Exon 20 of 27	NP_000594.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS3	ENST00000297494.8	TSL:1 MANE Select	c.2479G>A	p.Val827Met	missense	Exon 20 of 27	ENSP00000297494.3	P29474-1
	NOS3	ENST00000943234.1		c.2500G>A	p.Val834Met	missense	Exon 19 of 26	ENSP00000613293.1
	NOS3	ENST00000908206.1		c.2479G>A	p.Val827Met	missense	Exon 19 of 26	ENSP00000578265.1

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 504 AN: 152148 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00263

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00509

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00313 AC: 440 AN: 140414 AF XY: 0.00299

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00458

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00456 AC: 6350 AN: 1391310 Hom.: 17 Cov.: 35 AF XY: 0.00460 AC XY: 3153 AN XY: 685926

African (AFR) AF: 0.000604 AC: 19 AN: 31468

American (AMR) AF: 0.00288 AC: 102 AN: 35450

Ashkenazi Jewish (ASJ) AF: 0.000400 AC: 10 AN: 25020

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35676

South Asian (SAS) AF: 0.00428 AC: 338 AN: 78882

European-Finnish (FIN) AF: 0.00168 AC: 76 AN: 45248

Middle Eastern (MID) AF: 0.00167 AC: 8 AN: 4786

European-Non Finnish (NFE) AF: 0.00517 AC: 5572 AN: 1077086

Other (OTH) AF: 0.00388 AC: 224 AN: 57694

GnomAD4 genome AF: 0.00330 AC: 503 AN: 152266 Hom.: 0 Cov.: 31 AF XY: 0.00333 AC XY: 248 AN XY: 74440

African (AFR) AF: 0.000674 AC: 28 AN: 41548

American (AMR) AF: 0.00333 AC: 51 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4820

European-Finnish (FIN) AF: 0.00263 AC: 28 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00509 AC: 346 AN: 68010

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00353 Hom.: 2

Bravo AF: 0.00323

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000259 AC: 1

ESP6500EA AF: 0.00314 AC: 24

ExAC AF: 0.00141 AC: 103

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.25
Sift	Benign	0.050	D
Sift4G	Uncertain	0.033	D
Polyphen		0.48	P
Vest4		0.20
MVP		0.74
MPC		0.91
ClinPred		0.032	T
GERP RS		-0.10
Varity_R		0.13
gMVP		0.37
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs3918232; hg19: chr7-150706640; COSMIC: COSV52489695; COSMIC: COSV52489695;