rs1800781

Variant names:

• chr7-150995356-G-A
• rs1800781
• NM_000603.5:c.270+42G>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.270+42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,406,146 control chromosomes in the GnomAD database, including 14,546 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1309 hom., cov: 32)
  • Exomes 𝑓: 0.14 (13237 hom.)
• Consequence: NOS3 NM_000603.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.813
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-150995356-G-A is Benign according to our data. Variant chr7-150995356-G-A is described in ClinVar as Benign. ClinVar VariationId is 1229830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS3	NM_000603.5	c.270+42G>A		intron_variant	Intron 3 of 26	ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1	c.270+42G>A		intron_variant	Intron 2 of 13		NP_001153583.1
NOS3	NM_001160110.1	c.270+42G>A		intron_variant	Intron 2 of 13		NP_001153582.1
NOS3	NM_001160109.2	c.270+42G>A		intron_variant	Intron 2 of 13		NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8	c.270+42G>A		intron_variant	Intron 3 of 26	1	NM_000603.5	ENSP00000297494.3
NOS3	ENST00000484524.5	c.270+42G>A		intron_variant	Intron 2 of 13	1		ENSP00000420215.1
NOS3	ENST00000467517.1	c.270+42G>A		intron_variant	Intron 2 of 13	1		ENSP00000420551.1
NOS3	ENST00000461406.5	c.-37+42G>A		intron_variant	Intron 2 of 23	2		ENSP00000417143.1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17153 AN: 151960 Hom.: 1310 Cov.: 32

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0953

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.132 AC: 28703 AN: 217458 AF XY: 0.137

Gnomad AFR exome AF: 0.0265

Gnomad AMR exome AF: 0.0757

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.105

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.141 AC: 177377 AN: 1254068 Hom.: 13237 Cov.: 16 AF XY: 0.143 AC XY: 90055 AN XY: 629072

African (AFR) AF: 0.0247 AC: 716 AN: 29036

American (AMR) AF: 0.0776 AC: 3255 AN: 41940

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 3784 AN: 24066

East Asian (EAS) AF: 0.108 AC: 4026 AN: 37446

South Asian (SAS) AF: 0.146 AC: 11646 AN: 79822

European-Finnish (FIN) AF: 0.174 AC: 8888 AN: 51022

Middle Eastern (MID) AF: 0.146 AC: 783 AN: 5352

European-Non Finnish (NFE) AF: 0.147 AC: 137244 AN: 932326

Other (OTH) AF: 0.133 AC: 7035 AN: 53058

GnomAD4 genome AF: 0.113 AC: 17143 AN: 152078 Hom.: 1309 Cov.: 32 AF XY: 0.114 AC XY: 8458 AN XY: 74350

African (AFR) AF: 0.0268 AC: 1111 AN: 41476

American (AMR) AF: 0.0951 AC: 1453 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 557 AN: 3470

East Asian (EAS) AF: 0.107 AC: 550 AN: 5164

South Asian (SAS) AF: 0.154 AC: 743 AN: 4820

European-Finnish (FIN) AF: 0.183 AC: 1946 AN: 10622

Middle Eastern (MID) AF: 0.154 AC: 45 AN: 292

European-Non Finnish (NFE) AF: 0.153 AC: 10396 AN: 67932

Other (OTH) AF: 0.115 AC: 243 AN: 2106

Alfa AF: 0.141 Hom.: 337

Bravo AF: 0.101

Asia WGS AF: 0.122 AC: 422 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.4
DANN	Benign	0.78
PhyloP100		-0.81
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800781; hg19: chr7-150692444; COSMIC: COSV52490200;