NM_000620.5:c.-421+4994G>A

Variant names:

• chr12-117356518-C-T
• rs17509231
• NM_000620.5:c.-421+4994G>A

Variant summary

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

The NM_000620.5(NOS1):​c.-421+4994G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 152,276 control chromosomes in the GnomAD database, including 1,038 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 (1038 hom., cov: 33)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0280
• Publications: 7 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.-421+4994G>A		intron_variant	Intron 1 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.-421+4994G>A		intron_variant	Intron 1 of 29		NP_001191147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.-421+4994G>A		intron_variant	Intron 1 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000618760.4	c.-421+4994G>A		intron_variant	Intron 1 of 29	5		ENSP00000477999.1
NOS1	ENST00000477584.1	n.118+4994G>A		intron_variant	Intron 1 of 1	2
NOS1	ENST00000549189.1	n.471-25029G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17015 AN: 152158 Hom.: 1039 Cov.: 33

Gnomad AFR AF: 0.0888

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0773

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.0431

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.111

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

GnomAD4 genome AF: 0.112 AC: 17008 AN: 152276 Hom.: 1038 Cov.: 33 AF XY: 0.112 AC XY: 8314 AN XY: 74450

African (AFR) AF: 0.0885 AC: 3680 AN: 41564

American (AMR) AF: 0.0772 AC: 1181 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 421 AN: 3472

East Asian (EAS) AF: 0.0432 AC: 224 AN: 5184

South Asian (SAS) AF: 0.114 AC: 551 AN: 4826

European-Finnish (FIN) AF: 0.138 AC: 1458 AN: 10598

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

European-Non Finnish (NFE) AF: 0.135 AC: 9167 AN: 68006

Other (OTH) AF: 0.110 AC: 233 AN: 2116

Alfa AF: 0.126 Hom.: 2051

Bravo AF: 0.106

Asia WGS AF: 0.0680 AC: 237 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.43
PhyloP100		-0.028
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: rs17509231; hg19: chr12-117794323;