12-117275960-C-T

Variant names:

• chr12-117275960-C-T
• rs7139256
• NM_000620.5:c.1664+1999G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000620.5(NOS1):​c.1664+1999G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 152,112 control chromosomes in the GnomAD database, including 52,871 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 0.83 (52871 hom., cov: 31)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.43
• Publications: 5 publications found

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]

NOS1 Gene-Disease associations (from GenCC):

• idiopathic achalasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.894 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.1664+1999G>A		intron_variant	Intron 9 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.1664+1999G>A		intron_variant	Intron 9 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.656+1999G>A		intron_variant	Intron 8 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.656+1999G>A		intron_variant	Intron 8 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.1664+1999G>A		intron_variant	Intron 9 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.1664+1999G>A		intron_variant	Intron 8 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.1664+1999G>A		intron_variant	Intron 9 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.833 AC: 126564 AN: 151994 Hom.: 52817 Cov.: 31

Gnomad AFR AF: 0.901

Gnomad AMI AF: 0.831

Gnomad AMR AF: 0.826

Gnomad ASJ AF: 0.808

Gnomad EAS AF: 0.838

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.786

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.800

Gnomad OTH AF: 0.821

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.833 AC: 126674 AN: 152112 Hom.: 52871 Cov.: 31 AF XY: 0.831 AC XY: 61764 AN XY: 74336

African (AFR) AF: 0.902 AC: 37419 AN: 41506

American (AMR) AF: 0.826 AC: 12624 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.808 AC: 2804 AN: 3470

East Asian (EAS) AF: 0.839 AC: 4330 AN: 5162

South Asian (SAS) AF: 0.845 AC: 4054 AN: 4800

European-Finnish (FIN) AF: 0.786 AC: 8305 AN: 10564

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.800 AC: 54418 AN: 68006

Other (OTH) AF: 0.820 AC: 1733 AN: 2114

Alfa AF: 0.811 Hom.: 87285

Bravo AF: 0.839

Asia WGS AF: 0.801 AC: 2787 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.033
DANN	Benign	0.60
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7139256; hg19: chr12-117713765;