rs3918227

Positions:

• chr7-151003858-C-A
• chr7-151003858-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001160111.1(NOS3):​c.*570C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0771 in 396,480 control chromosomes in the GnomAD database, including 1,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (491 hom., cov: 32)
  • Exomes 𝑓: 0.083 (946 hom.)
• Consequence: NOS3 NM_001160111.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.968

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 7-151003858-C-A is Benign according to our data. Variant chr7-151003858-C-A is described in ClinVar as [Benign]. Clinvar id is 1227867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS3	NM_000603.5	c.1752+1554C>A		intron_variant		ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1	c.*570C>A		3_prime_UTR_variant	14/14		NP_001153583.1
NOS3	NM_001160110.1	c.*455C>A		3_prime_UTR_variant	14/14		NP_001153582.1
NOS3	NM_001160109.2	c.*163C>A		3_prime_UTR_variant	14/14		NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000484524.5	c.*570C>A		3_prime_UTR_variant	14/14	1		ENSP00000420215.1
NOS3	ENST00000467517.1	c.*455C>A		3_prime_UTR_variant	14/14	1		ENSP00000420551.1
NOS3	ENST00000297494.8	c.1752+1554C>A		intron_variant		1	NM_000603.5	ENSP00000297494.3
NOS3	ENST00000461406.5	c.1134+1554C>A		intron_variant		2		ENSP00000417143.1

Frequencies

GnomAD3 genomes AF: 0.0684 AC: 10400 AN: 151996 Hom.: 492 Cov.: 32

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0512

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.0719

Gnomad SAS AF: 0.0625

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0954

Gnomad OTH AF: 0.0507

GnomAD4 exome AF: 0.0825 AC: 20166 AN: 244366 Hom.: 946 Cov.: 0 AF XY: 0.0821 AC XY: 11088 AN XY: 135092

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.0492

Gnomad4 ASJ exome AF: 0.0142

Gnomad4 EAS exome AF: 0.0717

Gnomad4 SAS exome AF: 0.0750

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.0953

Gnomad4 OTH exome AF: 0.0740

GnomAD4 genome AF: 0.0683 AC: 10393 AN: 152114 Hom.: 491 Cov.: 32 AF XY: 0.0703 AC XY: 5227 AN XY: 74362

Gnomad4 AFR AF: 0.0174

Gnomad4 AMR AF: 0.0510

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.0717

Gnomad4 SAS AF: 0.0623

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.0954

Gnomad4 OTH AF: 0.0497

Alfa AF: 0.0803 Hom.: 804

Bravo AF: 0.0583

Asia WGS AF: 0.0620 AC: 216 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.6
DANN	Benign	0.72

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: rs3918227; hg19: chr7-150700946;