12-117258236-T-G

Variant names:

• chr12-117258236-T-G
• rs2682820
• NM_000620.5:c.2531+161A>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.2531+161A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.55 in 152,054 control chromosomes in the GnomAD database, including 25,497 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 0.55 (25497 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.217
• Publications: 2 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.807 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	NM_000620.5	MANE Select	c.2531+161A>C		intron	N/A	NP_000611.1
	NOS1	NM_001204218.2		c.2531+161A>C		intron	N/A	NP_001191147.1
	NOS1	NM_001204213.2		c.1523+161A>C		intron	N/A	NP_001191142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.2531+161A>C		intron	N/A	ENSP00000320758.6
	NOS1	ENST00000338101.8	TSL:5	c.2531+161A>C		intron	N/A	ENSP00000337459.4
	NOS1	ENST00000618760.4	TSL:5	c.2531+161A>C		intron	N/A	ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.550 AC: 83528 AN: 151936 Hom.: 25424 Cov.: 32

Gnomad AFR AF: 0.814

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.626

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.534

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

GnomAD4 genome AF: 0.550 AC: 83662 AN: 152054 Hom.: 25497 Cov.: 32 AF XY: 0.550 AC XY: 40901 AN XY: 74310

African (AFR) AF: 0.814 AC: 33774 AN: 41490

American (AMR) AF: 0.622 AC: 9505 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1476 AN: 3466

East Asian (EAS) AF: 0.626 AC: 3221 AN: 5142

South Asian (SAS) AF: 0.465 AC: 2239 AN: 4818

European-Finnish (FIN) AF: 0.376 AC: 3982 AN: 10582

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27813 AN: 67968

Other (OTH) AF: 0.538 AC: 1135 AN: 2108

Alfa AF: 0.489 Hom.: 6482

Bravo AF: 0.582

Asia WGS AF: 0.567 AC: 1972 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.4
DANN	Benign	0.54
PhyloP100		-0.22
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: rs2682820; hg19: chr12-117696041;