NM_000603.5:c.2113-176G>A

Variant names:

• chr7-151008754-G-A
• rs3918196
• NM_000603.5:c.2113-176G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000603.5(NOS3):​c.2113-176G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0775 in 657,914 control chromosomes in the GnomAD database, including 2,376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (470 hom., cov: 33)
  • Exomes 𝑓: 0.079 (1906 hom.)
• Consequence: NOS3 NM_000603.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.729
• Publications: 6 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 (BayesDel_noAF=-0.81).
• BP6: Variant 7-151008754-G-A is Benign according to our data. Variant chr7-151008754-G-A is described in ClinVar as Benign. ClinVar VariationId is 1261260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS3	NM_000603.5	MANE Select	c.2113-176G>A		intron	N/A	NP_000594.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS3	ENST00000297494.8	TSL:1 MANE Select	c.2113-176G>A		intron	N/A	ENSP00000297494.3
	NOS3	ENST00000461406.5	TSL:2	c.1495-176G>A		intron	N/A	ENSP00000417143.1
	NOS3	ENST00000475017.1	TSL:2	c.-185G>A		upstream_gene	N/A	ENSP00000418245.1

Frequencies

GnomAD3 genomes AF: 0.0711 AC: 10822 AN: 152154 Hom.: 469 Cov.: 33

Gnomad AFR AF: 0.0510

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.0653

Gnomad ASJ AF: 0.0919

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0861

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0689

Gnomad OTH AF: 0.0789

GnomAD4 exome AF: 0.0794 AC: 40171 AN: 505642 Hom.: 1906 AF XY: 0.0806 AC XY: 20917 AN XY: 259540

African (AFR) AF: 0.0483 AC: 631 AN: 13070

American (AMR) AF: 0.0695 AC: 1041 AN: 14982

Ashkenazi Jewish (ASJ) AF: 0.0905 AC: 1233 AN: 13624

East Asian (EAS) AF: 0.185 AC: 5397 AN: 29118

South Asian (SAS) AF: 0.106 AC: 4032 AN: 38032

European-Finnish (FIN) AF: 0.0942 AC: 2791 AN: 29634

Middle Eastern (MID) AF: 0.139 AC: 288 AN: 2076

European-Non Finnish (NFE) AF: 0.0664 AC: 22410 AN: 337522

Other (OTH) AF: 0.0851 AC: 2348 AN: 27584

GnomAD4 genome AF: 0.0711 AC: 10828 AN: 152272 Hom.: 470 Cov.: 33 AF XY: 0.0733 AC XY: 5455 AN XY: 74446

African (AFR) AF: 0.0510 AC: 2118 AN: 41562

American (AMR) AF: 0.0649 AC: 993 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0919 AC: 319 AN: 3472

East Asian (EAS) AF: 0.168 AC: 867 AN: 5168

South Asian (SAS) AF: 0.104 AC: 503 AN: 4832

European-Finnish (FIN) AF: 0.0861 AC: 914 AN: 10610

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0689 AC: 4685 AN: 68004

Other (OTH) AF: 0.0847 AC: 179 AN: 2114

Alfa AF: 0.0698 Hom.: 475

Bravo AF: 0.0693

Asia WGS AF: 0.169 AC: 586 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.90
PhyloP100		0.73
PromoterAI		-0.11	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs3918196; hg19: chr7-150705842;