rs3918201

Variant names:

• chr7-151010256-G-T
• rs3918201
• NM_000603.5:c.2654G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-151010256-G-T
• chr7-151010256-G-A
• chr7-151010256-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000603.5(NOS3):​c.2654G>T​(p.Arg885Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,613,000 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (34 hom., cov: 34)
  • Exomes 𝑓: 0.0013 (21 hom.)
• Consequence: NOS3 NM_000603.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.02
• Publications: 21 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003750503).
• BP6: Variant 7-151010256-G-T is Benign according to our data. Variant chr7-151010256-G-T is described in ClinVar as Benign. ClinVar VariationId is 792094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0102 (1548/152362) while in subpopulation AFR AF = 0.035 (1456/41578). AF 95% confidence interval is 0.0335. There are 34 homozygotes in GnomAd4. There are 740 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1548 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.2654G>T	p.Arg885Met	missense	Exon 21 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.2654G>T	p.Arg885Met	missense	Exon 21 of 27	ENSP00000297494.3	P29474-1
	NOS3	ENST00000943234.1		c.2675G>T	p.Arg892Met	missense	Exon 20 of 26	ENSP00000613293.1
	NOS3	ENST00000908206.1		c.2654G>T	p.Arg885Met	missense	Exon 20 of 26	ENSP00000578265.1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1537 AN: 152244 Hom.: 33 Cov.: 34

Gnomad AFR AF: 0.0349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00296 AC: 739 AN: 249946 AF XY: 0.00228

Gnomad AFR exome AF: 0.0359

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00360

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000346

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00127 AC: 1851 AN: 1460638 Hom.: 21 Cov.: 32 AF XY: 0.00112 AC XY: 814 AN XY: 726652

African (AFR) AF: 0.0374 AC: 1252 AN: 33454

American (AMR) AF: 0.00190 AC: 85 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00283 AC: 74 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86196

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53080

Middle Eastern (MID) AF: 0.00595 AC: 31 AN: 5212

European-Non Finnish (NFE) AF: 0.000181 AC: 201 AN: 1111872

Other (OTH) AF: 0.00320 AC: 193 AN: 60312

GnomAD4 genome AF: 0.0102 AC: 1548 AN: 152362 Hom.: 34 Cov.: 34 AF XY: 0.00993 AC XY: 740 AN XY: 74500

African (AFR) AF: 0.0350 AC: 1456 AN: 41578

American (AMR) AF: 0.00300 AC: 46 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68030

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00355 Hom.: 24

Bravo AF: 0.0120

ESP6500AA AF: 0.0345 AC: 152

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00361 AC: 438

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.0
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.10
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Polyphen		0.0020	B
Vest4		0.22
MVP		0.74
MPC		0.74
ClinPred		0.048	T
GERP RS		4.4
Varity_R		0.077
gMVP		0.34
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -44

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3918201; hg19: chr7-150707344;