12-117227525-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000620.5(NOS1):c.3522G>A(p.Leu1174=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,612,798 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (5 hom., cov: 32)
  • Exomes 𝑓: 0.011 (146 hom.)
• Consequence: NOS1 NM_000620.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.489

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 12-117227525-C-T is Benign according to our data. Variant chr12-117227525-C-T is described in ClinVar as [Benign]. Clinvar id is 774486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.489 with no splicing effect.
• BS2: High AC in GnomAd at 1110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS1	NM_000620.5	c.3522G>A	p.Leu1174=	synonymous_variant	23/29	ENST00000317775.11
NOS1	NM_001204218.2	c.3624G>A	p.Leu1208=	synonymous_variant	24/30
NOS1	NM_001204213.2	c.2514G>A	p.Leu838=	synonymous_variant	22/28
NOS1	NM_001204214.2	c.2514G>A	p.Leu838=	synonymous_variant	22/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS1	ENST00000317775.11	c.3522G>A	p.Leu1174=	synonymous_variant	23/29	1	NM_000620.5	P1
NOS1	ENST00000338101.8	c.3624G>A	p.Leu1208=	synonymous_variant	23/29	5
NOS1	ENST00000618760.4	c.3624G>A	p.Leu1208=	synonymous_variant	24/30	5

Frequencies

GnomAD3 genomes AF: 0.00730 AC: 1110 AN: 152112 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00622

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00664 AC: 1647 AN: 248170 Hom.: 13 AF XY: 0.00644 AC XY: 867 AN XY: 134590

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.00268

Gnomad ASJ exome AF: 0.00383

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00119

Gnomad FIN exome AF: 0.00466

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00648

GnomAD4 exome AF: 0.0115 AC: 16769 AN: 1460568 Hom.: 146 Cov.: 32 AF XY: 0.0110 AC XY: 8008 AN XY: 726502

Gnomad4 AFR exome AF: 0.00227

Gnomad4 AMR exome AF: 0.00269

Gnomad4 ASJ exome AF: 0.00365

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.00547

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.00729 AC: 1109 AN: 152230 Hom.: 5 Cov.: 32 AF XY: 0.00633 AC XY: 471 AN XY: 74422

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00622

Gnomad4 NFE AF: 0.0130

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00952 Hom.: 2

Bravo AF: 0.00667

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0105

EpiControl AF: 0.0101

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NOS1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2019

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	6.0
Dann	Benign	0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs34375182; hg19: chr12-117665330;