12-117256215-C-T

Variant names:

• chr12-117256215-C-T
• rs12829185
• NM_000620.5:c.2531+2182G>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.2531+2182G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 151,044 control chromosomes in the GnomAD database, including 2,616 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 0.18 (2616 hom., cov: 30)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.415
• Publications: 12 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.2531+2182G>A		intron_variant	Intron 16 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.2532-178G>A		intron_variant	Intron 16 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.1523+2182G>A		intron_variant	Intron 15 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.1523+2182G>A		intron_variant	Intron 15 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.2531+2182G>A		intron_variant	Intron 16 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.2532-178G>A		intron_variant	Intron 15 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.2532-178G>A		intron_variant	Intron 16 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26462 AN: 150938 Hom.: 2615 Cov.: 30

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.299

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.202

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

GnomAD4 genome AF: 0.175 AC: 26475 AN: 151044 Hom.: 2616 Cov.: 30 AF XY: 0.176 AC XY: 13003 AN XY: 73728

African (AFR) AF: 0.101 AC: 4134 AN: 40968

American (AMR) AF: 0.193 AC: 2913 AN: 15092

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 960 AN: 3464

East Asian (EAS) AF: 0.282 AC: 1437 AN: 5100

South Asian (SAS) AF: 0.190 AC: 908 AN: 4784

European-Finnish (FIN) AF: 0.157 AC: 1637 AN: 10450

Middle Eastern (MID) AF: 0.310 AC: 90 AN: 290

European-Non Finnish (NFE) AF: 0.203 AC: 13773 AN: 67892

Other (OTH) AF: 0.205 AC: 429 AN: 2094

Alfa AF: 0.189 Hom.: 5071

Bravo AF: 0.171

Asia WGS AF: 0.222 AC: 771 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.7
DANN	Benign	0.56
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs12829185; hg19: chr12-117694020;