chr12-117264079-G-A

Variant names:

• chr12-117264079-G-A
• rs2293055
• NM_000620.5:c.2137-105C>T

Variant summary

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

The NM_000620.5(NOS1):​c.2137-105C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0805 in 761,228 control chromosomes in the GnomAD database, including 3,047 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 0.079 (606 hom., cov: 27)
  • Exomes 𝑓: 0.081 (2441 hom.)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.143
• Publications: 13 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 (NFE) allele frequency at 95% confidence interval = 0.1 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.2137-105C>T		intron	N/A	NP_000611.1
	NOS1	NM_001204218.2		c.2137-105C>T		intron	N/A	NP_001191147.1
	NOS1	NM_001204213.2		c.1129-105C>T		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.2137-105C>T		intron	N/A	ENSP00000320758.6
	NOS1	ENST00000338101.8	TSL:5	c.2137-105C>T		intron	N/A	ENSP00000337459.4
	NOS1	ENST00000618760.4	TSL:5	c.2137-105C>T		intron	N/A	ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.0787 AC: 11816 AN: 150082 Hom.: 606 Cov.: 27

Gnomad AFR AF: 0.0422

Gnomad AMI AF: 0.0499

Gnomad AMR AF: 0.0672

Gnomad ASJ AF: 0.0848

Gnomad EAS AF: 0.0754

Gnomad SAS AF: 0.0618

Gnomad FIN AF: 0.0931

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0931

GnomAD4 exome AF: 0.0809 AC: 49432 AN: 611042 Hom.: 2441 AF XY: 0.0807 AC XY: 26078 AN XY: 323012

African (AFR) AF: 0.0392 AC: 584 AN: 14888

American (AMR) AF: 0.0511 AC: 1772 AN: 34682

Ashkenazi Jewish (ASJ) AF: 0.0681 AC: 1049 AN: 15396

East Asian (EAS) AF: 0.0656 AC: 1693 AN: 25826

South Asian (SAS) AF: 0.0598 AC: 3132 AN: 52412

European-Finnish (FIN) AF: 0.0905 AC: 3375 AN: 37306

Middle Eastern (MID) AF: 0.0592 AC: 167 AN: 2822

European-Non Finnish (NFE) AF: 0.0886 AC: 35392 AN: 399266

Other (OTH) AF: 0.0797 AC: 2268 AN: 28444

GnomAD4 genome AF: 0.0787 AC: 11820 AN: 150186 Hom.: 606 Cov.: 27 AF XY: 0.0782 AC XY: 5730 AN XY: 73252

African (AFR) AF: 0.0421 AC: 1709 AN: 40600

American (AMR) AF: 0.0670 AC: 1010 AN: 15068

Ashkenazi Jewish (ASJ) AF: 0.0848 AC: 293 AN: 3456

East Asian (EAS) AF: 0.0756 AC: 381 AN: 5042

South Asian (SAS) AF: 0.0625 AC: 296 AN: 4734

European-Finnish (FIN) AF: 0.0931 AC: 968 AN: 10402

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.102 AC: 6911 AN: 67606

Other (OTH) AF: 0.0926 AC: 193 AN: 2084

Alfa AF: 0.0921 Hom.: 1499

Bravo AF: 0.0734

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.29
DANN	Benign	0.77
PhyloP100		0.14
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: rs2293055; hg19: chr12-117701884; COSMIC: COSV57608897;