rs3741475

Variant names:

• chr12-117232109-G-A
• rs3741475
• NM_000620.5:c.3258C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-117232109-G-A
• chr12-117232109-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000620.5(NOS1):​c.3258C>T​(p.Asp1086Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,611,444 control chromosomes in the GnomAD database, including 36,971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.23 (4120 hom., cov: 31)
  • Exomes 𝑓: 0.21 (32851 hom.)
• Consequence: NOS1 NM_000620.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.259
• Publications: 37 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 12-117232109-G-A is Benign according to our data. Variant chr12-117232109-G-A is described in ClinVar as Benign. ClinVar VariationId is 3061017.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.259 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.313 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.3258C>T	p.Asp1086Asp	synonymous	Exon 22 of 29	NP_000611.1
	NOS1	NM_001204218.2		c.3360C>T	p.Asp1120Asp	synonymous	Exon 23 of 30	NP_001191147.1
	NOS1	NM_001204213.2		c.2250C>T	p.Asp750Asp	synonymous	Exon 21 of 28	NP_001191142.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.3258C>T	p.Asp1086Asp	synonymous	Exon 22 of 29	ENSP00000320758.6
	NOS1	ENST00000338101.8	TSL:5	c.3360C>T	p.Asp1120Asp	synonymous	Exon 22 of 29	ENSP00000337459.4
	NOS1	ENST00000618760.4	TSL:5	c.3360C>T	p.Asp1120Asp	synonymous	Exon 23 of 30	ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34391 AN: 151852 Hom.: 4106 Cov.: 31

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.344

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.247

GnomAD2 exomes AF: 0.220 AC: 54746 AN: 248876 AF XY: 0.222

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.274

Gnomad EAS exome AF: 0.330

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.209 AC: 304892 AN: 1459474 Hom.: 32851 Cov.: 33 AF XY: 0.211 AC XY: 153112 AN XY: 726056

African (AFR) AF: 0.269 AC: 8986 AN: 33394

American (AMR) AF: 0.182 AC: 8129 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 7177 AN: 26130

East Asian (EAS) AF: 0.331 AC: 13157 AN: 39694

South Asian (SAS) AF: 0.246 AC: 21227 AN: 86162

European-Finnish (FIN) AF: 0.166 AC: 8857 AN: 53380

Middle Eastern (MID) AF: 0.313 AC: 1302 AN: 4154

European-Non Finnish (NFE) AF: 0.200 AC: 221927 AN: 1111660

Other (OTH) AF: 0.235 AC: 14130 AN: 60196

GnomAD4 genome AF: 0.227 AC: 34436 AN: 151970 Hom.: 4120 Cov.: 31 AF XY: 0.227 AC XY: 16856 AN XY: 74294

African (AFR) AF: 0.262 AC: 10835 AN: 41416

American (AMR) AF: 0.218 AC: 3324 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 978 AN: 3464

East Asian (EAS) AF: 0.326 AC: 1679 AN: 5150

South Asian (SAS) AF: 0.238 AC: 1148 AN: 4814

European-Finnish (FIN) AF: 0.156 AC: 1646 AN: 10578

Middle Eastern (MID) AF: 0.346 AC: 101 AN: 292

European-Non Finnish (NFE) AF: 0.206 AC: 14014 AN: 67962

Other (OTH) AF: 0.253 AC: 534 AN: 2108

Alfa AF: 0.216 Hom.: 7322

Bravo AF: 0.230

Asia WGS AF: 0.325 AC: 1129 AN: 3478

EpiCase AF: 0.223

EpiControl AF: 0.226

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	NOS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.73
DANN	Benign	0.75
PhyloP100		-0.26
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3741475; hg19: chr12-117669914; COSMIC: COSV57608414;