12-117286288-T-C

Position:

• chr12-117286288-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000620.5(NOS1):​c.1128-22A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000364 in 1,613,272 control chromosomes in the GnomAD database, including 3 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 0.00036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.80

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS2: High AC in GnomAd4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS1	NM_000620.5	c.1128-22A>G		intron_variant		ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.1128-22A>G		intron_variant			NP_001191147.1
NOS1	NM_001204213.2	c.120-22A>G		intron_variant			NP_001191142.1
NOS1	NM_001204214.2	c.120-22A>G		intron_variant			NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.1128-22A>G		intron_variant		1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.1128-22A>G		intron_variant		5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.1128-22A>G		intron_variant		5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152194 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00654

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000580 AC: 144 AN: 248442 Hom.: 1 AF XY: 0.000571 AC XY: 77 AN XY: 134766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00502

Gnomad SAS exome AF: 0.000688

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.000222

Gnomad OTH exome AF: 0.000829

GnomAD4 exome AF: 0.000364 AC: 532 AN: 1460960 Hom.: 2 Cov.: 30 AF XY: 0.000424 AC XY: 308 AN XY: 726638

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00822

Gnomad4 SAS exome AF: 0.000627

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152312 Hom.: 1 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74490

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00675

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.000351

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.0010
DANN	Benign	0.51

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: rs2293049; hg19: chr12-117724093;