rs2293055

chr12-117264079-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000620.5(NOS1):c.2137-105C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0805 in 761,228 control chromosomes in the GnomAD database, including 3,047 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 0.079 (606 hom., cov: 27)
  • Exomes 𝑓: 0.081 (2441 hom.)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS1	NM_000620.5	c.2137-105C>T		intron_variant		ENST00000317775.11
NOS1	NM_001204213.2	c.1129-105C>T		intron_variant
NOS1	NM_001204214.2	c.1129-105C>T		intron_variant
NOS1	NM_001204218.2	c.2137-105C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS1	ENST00000317775.11	c.2137-105C>T		intron_variant		1	NM_000620.5	P1
NOS1	ENST00000338101.8	c.2137-105C>T		intron_variant		5
NOS1	ENST00000618760.4	c.2137-105C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0787 AC: 11816 AN: 150082 Hom.: 606 Cov.: 27

Gnomad AFR AF: 0.0422

Gnomad AMI AF: 0.0499

Gnomad AMR AF: 0.0672

Gnomad ASJ AF: 0.0848

Gnomad EAS AF: 0.0754

Gnomad SAS AF: 0.0618

Gnomad FIN AF: 0.0931

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0931

GnomAD4 exome AF: 0.0809 AC: 49432 AN: 611042 Hom.: 2441 AF XY: 0.0807 AC XY: 26078 AN XY: 323012

Gnomad4 AFR exome AF: 0.0392

Gnomad4 AMR exome AF: 0.0511

Gnomad4 ASJ exome AF: 0.0681

Gnomad4 EAS exome AF: 0.0656

Gnomad4 SAS exome AF: 0.0598

Gnomad4 FIN exome AF: 0.0905

Gnomad4 NFE exome AF: 0.0886

Gnomad4 OTH exome AF: 0.0797

GnomAD4 genome AF: 0.0787 AC: 11820 AN: 150186 Hom.: 606 Cov.: 27 AF XY: 0.0782 AC XY: 5730 AN XY: 73252

Gnomad4 AFR AF: 0.0421

Gnomad4 AMR AF: 0.0670

Gnomad4 ASJ AF: 0.0848

Gnomad4 EAS AF: 0.0756

Gnomad4 SAS AF: 0.0625

Gnomad4 FIN AF: 0.0931

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.0926

Alfa AF: 0.0943 Hom.: 1042

Bravo AF: 0.0734

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.29
Dann	Benign	0.77

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: rs2293055; hg19: chr12-117701884; COSMIC: COSV57608897;