12-117220186-G-T

Variant names:

• chr12-117220186-G-T
• rs2293044
• NM_000620.5:c.4059C>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000620.5(NOS1):​c.4059C>A​(p.Val1353Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,613,938 control chromosomes in the GnomAD database, including 467 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 (132 hom., cov: 32)
  • Exomes 𝑓: 0.012 (335 hom.)
• Consequence: NOS1 NM_000620.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.143

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 12-117220186-G-T is Benign according to our data. Variant chr12-117220186-G-T is described in ClinVar as [Benign]. Clinvar id is 3059998.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.143 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.4059C>A	p.Val1353Val	synonymous_variant	Exon 27 of 29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.4161C>A	p.Val1387Val	synonymous_variant	Exon 28 of 30		NP_001191147.1
NOS1	NM_001204213.2	c.3051C>A	p.Val1017Val	synonymous_variant	Exon 26 of 28		NP_001191142.1
NOS1	NM_001204214.2	c.3051C>A	p.Val1017Val	synonymous_variant	Exon 26 of 28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.4059C>A	p.Val1353Val	synonymous_variant	Exon 27 of 29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.4161C>A	p.Val1387Val	synonymous_variant	Exon 27 of 29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.4161C>A	p.Val1387Val	synonymous_variant	Exon 28 of 30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.0265 AC: 4027 AN: 152204 Hom.: 132 Cov.: 32

Gnomad AFR AF: 0.0690

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0197

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0500

Gnomad SAS AF: 0.0325

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00563

Gnomad OTH AF: 0.0253

GnomAD3 exomes AF: 0.0162 AC: 4048 AN: 249668 Hom.: 85 AF XY: 0.0163 AC XY: 2210 AN XY: 135246

Gnomad AFR exome AF: 0.0678

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.0462

Gnomad SAS exome AF: 0.0293

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.00602

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.0119 AC: 17390 AN: 1461616 Hom.: 335 Cov.: 31 AF XY: 0.0123 AC XY: 8910 AN XY: 727130

Gnomad4 AFR exome AF: 0.0696

Gnomad4 AMR exome AF: 0.0146

Gnomad4 ASJ exome AF: 0.000650

Gnomad4 EAS exome AF: 0.0738

Gnomad4 SAS exome AF: 0.0295

Gnomad4 FIN exome AF: 0.000207

Gnomad4 NFE exome AF: 0.00723

Gnomad4 OTH exome AF: 0.0132

GnomAD4 genome AF: 0.0265 AC: 4034 AN: 152322 Hom.: 132 Cov.: 32 AF XY: 0.0264 AC XY: 1963 AN XY: 74494

Gnomad4 AFR AF: 0.0690

Gnomad4 AMR AF: 0.0196

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0501

Gnomad4 SAS AF: 0.0329

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00563

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0115 Hom.: 22

Bravo AF: 0.0297

Asia WGS AF: 0.0380 AC: 130 AN: 3478

EpiCase AF: 0.00676

EpiControl AF: 0.00735

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

NOS1-related disorder Benign:1

Jan 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.2
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs2293044; hg19: chr12-117657991;