rs4767523

Variant names:

• chr12-117235597-T-G
• rs4767523
• NM_000620.5:c.3042-839A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000620.5(NOS1):​c.3042-839A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 152,224 control chromosomes in the GnomAD database, including 1,356 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1356 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.380
• Publications: 5 publications found

Genes affected

NOS1 (HGNC:7872): (nitric oxide synthase 1) The protein encoded by this gene belongs to the family of nitric oxide synthases, which synthesize nitric oxide from L-arginine. Nitric oxide is a reactive free radical, which acts as a biologic mediator in several processes, including neurotransmission, and antimicrobial and antitumoral activities. In the brain and peripheral nervous system, nitric oxide displays many properties of a neurotransmitter, and has been implicated in neurotoxicity associated with stroke and neurodegenerative diseases, neural regulation of smooth muscle, including peristalsis, and penile erection. This protein is ubiquitously expressed, with high level of expression in skeletal muscle. Multiple transcript variants that differ in the 5' UTR have been described for this gene but the full-length nature of these transcripts is not known. Additionally, alternatively spliced transcript variants encoding different isoforms (some testis-specific) have been found for this gene.[provided by RefSeq, Feb 2011]

NOS1 Gene-Disease associations (from GenCC):

• idiopathic achalasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.3042-839A>C		intron_variant	Intron 20 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.3144-839A>C		intron_variant	Intron 21 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.2034-839A>C		intron_variant	Intron 19 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.2034-839A>C		intron_variant	Intron 19 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.3042-839A>C		intron_variant	Intron 20 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.3144-839A>C		intron_variant	Intron 20 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.3144-839A>C		intron_variant	Intron 21 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17259 AN: 152106 Hom.: 1347 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.0553

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.0629

Gnomad FIN AF: 0.0734

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0970

Gnomad OTH AF: 0.112

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.114 AC: 17289 AN: 152224 Hom.: 1356 Cov.: 32 AF XY: 0.114 AC XY: 8482 AN XY: 74420

African (AFR) AF: 0.109 AC: 4528 AN: 41530

American (AMR) AF: 0.288 AC: 4401 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0553 AC: 192 AN: 3470

East Asian (EAS) AF: 0.0235 AC: 122 AN: 5186

South Asian (SAS) AF: 0.0622 AC: 300 AN: 4826

European-Finnish (FIN) AF: 0.0734 AC: 778 AN: 10594

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0970 AC: 6598 AN: 68014

Other (OTH) AF: 0.112 AC: 237 AN: 2114

Alfa AF: 0.108 Hom.: 167

Bravo AF: 0.133

Asia WGS AF: 0.0620 AC: 217 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.68
DANN	Benign	0.44
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4767523; hg19: chr12-117673402;