NM_000620.5:c.2601C>T

Variant names:

• chr12-117253685-G-A
• rs9658446
• NM_000620.5:c.2601C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000620.5(NOS1):​c.2601C>T​(p.Pro867Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00904 in 1,613,904 control chromosomes in the GnomAD database, including 320 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.026 (134 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (186 hom.)
• Consequence: NOS1 NM_000620.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -4.52
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 12-117253685-G-A is Benign according to our data. Variant chr12-117253685-G-A is described in ClinVar as Benign. ClinVar VariationId is 3055936.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0766 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.2601C>T	p.Pro867Pro	synonymous	Exon 17 of 29	NP_000611.1	P29475-1
	NOS1	NM_001204218.2		c.2703C>T	p.Pro901Pro	synonymous	Exon 18 of 30	NP_001191147.1	P29475-5
	NOS1	NM_001204213.2		c.1593C>T	p.Pro531Pro	synonymous	Exon 16 of 28	NP_001191142.1	P29475-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.2601C>T	p.Pro867Pro	synonymous	Exon 17 of 29	ENSP00000320758.6	P29475-1
	NOS1	ENST00000338101.8	TSL:5	c.2703C>T	p.Pro901Pro	synonymous	Exon 17 of 29	ENSP00000337459.4	P29475-5
	NOS1	ENST00000618760.4	TSL:5	c.2703C>T	p.Pro901Pro	synonymous	Exon 18 of 30	ENSP00000477999.1	P29475-5

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3935 AN: 151996 Hom.: 133 Cov.: 32

Gnomad AFR AF: 0.0789

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0202

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.0216

GnomAD2 exomes AF: 0.0122 AC: 3034 AN: 249510 AF XY: 0.0118

Gnomad AFR exome AF: 0.0852

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.000222

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.00416

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00728 AC: 10642 AN: 1461790 Hom.: 186 Cov.: 30 AF XY: 0.00756 AC XY: 5499 AN XY: 727216

African (AFR) AF: 0.0798 AC: 2670 AN: 33470

American (AMR) AF: 0.0105 AC: 471 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 271 AN: 26130

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39696

South Asian (SAS) AF: 0.0234 AC: 2021 AN: 86252

European-Finnish (FIN) AF: 0.000374 AC: 20 AN: 53420

Middle Eastern (MID) AF: 0.0205 AC: 118 AN: 5752

European-Non Finnish (NFE) AF: 0.00394 AC: 4379 AN: 1111960

Other (OTH) AF: 0.0114 AC: 686 AN: 60392

GnomAD4 genome AF: 0.0259 AC: 3941 AN: 152114 Hom.: 134 Cov.: 32 AF XY: 0.0253 AC XY: 1881 AN XY: 74370

African (AFR) AF: 0.0788 AC: 3271 AN: 41496

American (AMR) AF: 0.0136 AC: 207 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0202 AC: 97 AN: 4804

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10594

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00406 AC: 276 AN: 68008

Other (OTH) AF: 0.0213 AC: 45 AN: 2108

Alfa AF: 0.0147 Hom.: 45

Bravo AF: 0.0294

Asia WGS AF: 0.00953 AC: 34 AN: 3478

EpiCase AF: 0.00485

EpiControl AF: 0.00533

ClinVar

ClinVar submissions

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	-0.65
CADD	Benign	2.0
DANN	Benign	0.65
PhyloP100		-4.5
Mutation Taster		=97/3	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: rs9658446; hg19: chr12-117691490;