rs3918166

chr7-150996468-G-Achr7-150996468-G-Cchr7-150996468-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000603.5(NOS3):c.335G>A(p.Arg112Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,590,136 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.014 (45 hom., cov: 26)
  • Exomes 𝑓: 0.0018 (42 hom.)
• Consequence: NOS3 NM_000603.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.275

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025461912).
• BP6: Variant 7-150996468-G-A is Benign according to our data. Variant chr7-150996468-G-A is described in ClinVar as [Benign]. Clinvar id is 1182440.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0144 (2101/146008) while in subpopulation AFR AF= 0.0499 (1945/38956). AF 95% confidence interval is 0.0481. There are 45 homozygotes in gnomad4. There are 1011 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High AC in GnomAd at 2100 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS3	NM_000603.5	c.335G>A	p.Arg112Gln	missense_variant	4/27	ENST00000297494.8
NOS3	NM_001160111.1	c.335G>A	p.Arg112Gln	missense_variant	3/14
NOS3	NM_001160110.1	c.335G>A	p.Arg112Gln	missense_variant	3/14
NOS3	NM_001160109.2	c.335G>A	p.Arg112Gln	missense_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS3	ENST00000297494.8	c.335G>A	p.Arg112Gln	missense_variant	4/27	1	NM_000603.5	P1
NOS3	ENST00000484524.5	c.335G>A	p.Arg112Gln	missense_variant	3/14	1
NOS3	ENST00000467517.1	c.335G>A	p.Arg112Gln	missense_variant	3/14	1
NOS3	ENST00000461406.5	c.-37+1154G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2100 AN: 145902 Hom.: 45 Cov.: 26

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00698

Gnomad ASJ AF: 0.000583

Gnomad EAS AF: 0.000621

Gnomad SAS AF: 0.000901

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000376

Gnomad OTH AF: 0.0106

GnomAD3 exomes AF: 0.00391 AC: 848 AN: 216676 Hom.: 8 AF XY: 0.00309 AC XY: 365 AN XY: 118148

Gnomad AFR exome AF: 0.0541

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.000215

Gnomad EAS exome AF: 0.0000600

Gnomad SAS exome AF: 0.000179

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000554

Gnomad OTH exome AF: 0.00258

GnomAD4 exome AF: 0.00177 AC: 2559 AN: 1444128 Hom.: 42 Cov.: 34 AF XY: 0.00156 AC XY: 1120 AN XY: 716674

Gnomad4 AFR exome AF: 0.0516

Gnomad4 AMR exome AF: 0.00363

Gnomad4 ASJ exome AF: 0.000117

Gnomad4 EAS exome AF: 0.00125

Gnomad4 SAS exome AF: 0.000167

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000354

Gnomad4 OTH exome AF: 0.00355

GnomAD4 genome AF: 0.0144 AC: 2101 AN: 146008 Hom.: 45 Cov.: 26 AF XY: 0.0143 AC XY: 1011 AN XY: 70890

Gnomad4 AFR AF: 0.0499

Gnomad4 AMR AF: 0.00697

Gnomad4 ASJ AF: 0.000583

Gnomad4 EAS AF: 0.000623

Gnomad4 SAS AF: 0.000677

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000376

Gnomad4 OTH AF: 0.0105

Alfa AF: 0.00303 Hom.: 6

Bravo AF: 0.0173

ESP6500AA AF: 0.0449 AC: 194

ESP6500EA AF: 0.000586 AC: 5

ExAC AF: 0.00454 AC: 543

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.84	T;T;T
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.94	N;N;N
REVEL	Benign	0.050
Sift	Benign	0.57	T;T;T
Sift4G	Benign	0.46	T;T;T
Polyphen		0.79	P;.;.
Vest4		0.12
MVP		0.49
MPC		0.073
ClinPred		0.0075	T
GERP RS		3.9
Varity_R		0.080
gMVP		0.43

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: rs3918166; hg19: chr7-150693556;