chr12-117339567-T-C

Variant names:

• chr12-117339567-T-C
• rs1004356
• NM_000620.5:c.-420-8078A>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.-420-8078A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,198 control chromosomes in the GnomAD database, including 1,917 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 0.15 (1917 hom., cov: 33)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.08
• Publications: 10 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000620.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	NM_000620.5	MANE Select	c.-420-8078A>G		intron	N/A	NP_000611.1	P29475-1
	NOS1	NM_001204218.2		c.-420-8078A>G		intron	N/A	NP_001191147.1	P29475-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.-420-8078A>G		intron	N/A	ENSP00000320758.6	P29475-1
	NOS1	ENST00000618760.4	TSL:5	c.-420-8078A>G		intron	N/A	ENSP00000477999.1	P29475-5
	NOS1	ENST00000549189.1	TSL:3	n.471-8078A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23179 AN: 152080 Hom.: 1918 Cov.: 33

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.0531

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.149

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

GnomAD4 genome AF: 0.152 AC: 23175 AN: 152198 Hom.: 1917 Cov.: 33 AF XY: 0.151 AC XY: 11200 AN XY: 74404

African (AFR) AF: 0.123 AC: 5097 AN: 41528

American (AMR) AF: 0.108 AC: 1644 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 685 AN: 3470

East Asian (EAS) AF: 0.0534 AC: 277 AN: 5190

South Asian (SAS) AF: 0.116 AC: 559 AN: 4822

European-Finnish (FIN) AF: 0.189 AC: 1997 AN: 10586

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.183 AC: 12473 AN: 67994

Other (OTH) AF: 0.148 AC: 313 AN: 2112

Alfa AF: 0.173 Hom.: 3951

Bravo AF: 0.147

Asia WGS AF: 0.0790 AC: 277 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.89
PhyloP100		-2.1
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: rs1004356; hg19: chr12-117777372;