12-117309405-T-C

Position:

• chr12-117309405-T-C

Variant summary

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

The NM_001204214.2(NOS1):​c.-301A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 983,844 control chromosomes in the GnomAD database, including 8,483 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 0.14 (1637 hom., cov: 32)
  • Exomes 𝑓: 0.13 (6846 hom.)
• Consequence: NOS1 NM_001204214.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.539

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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS1	NM_000620.5	c.852+2061A>G		intron_variant		ENST00000317775.11	NP_000611.1
NOS1	NM_001204214.2	c.-301A>G		5_prime_UTR_variant	1/28		NP_001191143.1
NOS1	NM_001204218.2	c.852+2061A>G		intron_variant			NP_001191147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.852+2061A>G		intron_variant		1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.852+2061A>G		intron_variant		5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.852+2061A>G		intron_variant		5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20679 AN: 152020 Hom.: 1636 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.147

GnomAD4 exome AF: 0.126 AC: 104595 AN: 831706 Hom.: 6846 Cov.: 26 AF XY: 0.126 AC XY: 48407 AN XY: 384124

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.196

Gnomad4 ASJ exome AF: 0.141

Gnomad4 EAS exome AF: 0.252

Gnomad4 SAS exome AF: 0.252

Gnomad4 FIN exome AF: 0.109

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.136 AC: 20692 AN: 152138 Hom.: 1637 Cov.: 32 AF XY: 0.140 AC XY: 10408 AN XY: 74376

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.137

Gnomad4 EAS AF: 0.264

Gnomad4 SAS AF: 0.251

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.146

Alfa AF: 0.121 Hom.: 876

Bravo AF: 0.137

Asia WGS AF: 0.230 AC: 799 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.43

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: rs7298903; hg19: chr12-117747210;