12-117277815-G-A

Variant names:

• chr12-117277815-G-A
• rs2293052
• NM_000620.5:c.1664+144C>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.1664+144C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 950,458 control chromosomes in the GnomAD database, including 56,828 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 0.28 (7001 hom., cov: 31)
  • Exomes 𝑓: 0.35 (49827 hom.)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• Publications: 14 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.357 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.1664+144C>T		intron	N/A	NP_000611.1
	NOS1	NM_001204218.2		c.1664+144C>T		intron	N/A	NP_001191147.1
	NOS1	NM_001204213.2		c.656+144C>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.1664+144C>T		intron	N/A	ENSP00000320758.6
	NOS1	ENST00000338101.8	TSL:5	c.1664+144C>T		intron	N/A	ENSP00000337459.4
	NOS1	ENST00000618760.4	TSL:5	c.1664+144C>T		intron	N/A	ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42409 AN: 151792 Hom.: 7001 Cov.: 31

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.484

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.302

GnomAD4 exome AF: 0.347 AC: 277154 AN: 798548 Hom.: 49827 AF XY: 0.348 AC XY: 140213 AN XY: 403434

African (AFR) AF: 0.106 AC: 2033 AN: 19248

American (AMR) AF: 0.229 AC: 5088 AN: 22226

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 5274 AN: 14976

East Asian (EAS) AF: 0.232 AC: 7760 AN: 33448

South Asian (SAS) AF: 0.338 AC: 16563 AN: 49050

European-Finnish (FIN) AF: 0.371 AC: 13745 AN: 37034

Middle Eastern (MID) AF: 0.403 AC: 1016 AN: 2522

European-Non Finnish (NFE) AF: 0.366 AC: 213380 AN: 583242

Other (OTH) AF: 0.334 AC: 12295 AN: 36802

GnomAD4 genome AF: 0.279 AC: 42407 AN: 151910 Hom.: 7001 Cov.: 31 AF XY: 0.281 AC XY: 20879 AN XY: 74218

African (AFR) AF: 0.110 AC: 4576 AN: 41464

American (AMR) AF: 0.255 AC: 3893 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1244 AN: 3464

East Asian (EAS) AF: 0.259 AC: 1326 AN: 5126

South Asian (SAS) AF: 0.338 AC: 1624 AN: 4806

European-Finnish (FIN) AF: 0.386 AC: 4069 AN: 10546

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.361 AC: 24487 AN: 67916

Other (OTH) AF: 0.300 AC: 632 AN: 2108

Alfa AF: 0.323 Hom.: 1075

Bravo AF: 0.261

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.66
DANN	Benign	0.80
PhyloP100		-1.3
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: rs2293052; hg19: chr12-117715620; COSMIC: COSV57621377;