12-117348300-A-G

Position:

• chr12-117348300-A-G

Variant summary

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

The NM_000620.5(NOS1):​c.-421+13212T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 151,970 control chromosomes in the GnomAD database, including 12,374 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 0.39 (12371 hom., cov: 31)
  • Exomes 𝑓: 0.46 (3 hom.)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0760

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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS1	NM_000620.5	c.-421+13212T>C		intron_variant		ENST00000317775.11
NOS1	NM_001204218.2	c.-421+13212T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS1	ENST00000317775.11	c.-421+13212T>C		intron_variant		1	NM_000620.5	P1
NOS1	ENST00000618760.4	c.-421+13212T>C		intron_variant		5
NOS1	ENST00000477584.1	n.211T>C		non_coding_transcript_exon_variant	2/2	2
NOS1	ENST00000549189.1	n.471-16811T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59708 AN: 151828 Hom.: 12370 Cov.: 31

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.344

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.386

GnomAD4 exome AF: 0.458 AC: 11 AN: 24 Hom.: 3 Cov.: 0 AF XY: 0.500 AC XY: 8 AN XY: 16

Gnomad4 AFR exome AF: 1.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.444

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.393 AC: 59731 AN: 151946 Hom.: 12371 Cov.: 31 AF XY: 0.397 AC XY: 29471 AN XY: 74258

Gnomad4 AFR AF: 0.259

Gnomad4 AMR AF: 0.443

Gnomad4 ASJ AF: 0.408

Gnomad4 EAS AF: 0.568

Gnomad4 SAS AF: 0.411

Gnomad4 FIN AF: 0.466

Gnomad4 NFE AF: 0.439

Gnomad4 OTH AF: 0.388

Alfa AF: 0.430 Hom.: 12281

Bravo AF: 0.388

Asia WGS AF: 0.503 AC: 1747 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.3
DANN	Benign	0.64

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: rs1123425; hg19: chr12-117786105;