chr12-117300432-G-C

Variant names:

• chr12-117300432-G-C
• rs11612772
• NM_000620.5:c.853-10006C>G

Variant summary

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

The NM_000620.5(NOS1):​c.853-10006C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 152,040 control chromosomes in the GnomAD database, including 5,173 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 0.24 (5173 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.356
• Publications: 4 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.853-10006C>G		intron_variant	Intron 3 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.853-10006C>G		intron_variant	Intron 3 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.-157+1584C>G		intron_variant	Intron 2 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.-157+1584C>G		intron_variant	Intron 2 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.853-10006C>G		intron_variant	Intron 3 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.853-10006C>G		intron_variant	Intron 2 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.853-10006C>G		intron_variant	Intron 3 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37021 AN: 151922 Hom.: 5175 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.0560

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.239

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

GnomAD4 genome AF: 0.244 AC: 37031 AN: 152040 Hom.: 5173 Cov.: 32 AF XY: 0.241 AC XY: 17877 AN XY: 74290

African (AFR) AF: 0.126 AC: 5245 AN: 41500

American (AMR) AF: 0.305 AC: 4657 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1083 AN: 3464

East Asian (EAS) AF: 0.0564 AC: 292 AN: 5180

South Asian (SAS) AF: 0.185 AC: 890 AN: 4806

European-Finnish (FIN) AF: 0.292 AC: 3084 AN: 10558

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.308 AC: 20957 AN: 67960

Other (OTH) AF: 0.239 AC: 504 AN: 2112

Alfa AF: 0.145 Hom.: 283

Bravo AF: 0.244

Asia WGS AF: 0.127 AC: 449 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.0
DANN	Benign	0.66
PhyloP100		0.36
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: rs11612772; hg19: chr12-117738237; COSMIC: COSV57611121;