12-117294534-A-G

Variant names:

• chr12-117294534-A-G
• rs532967
• NM_000620.5:c.853-4108T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000620.5(NOS1):​c.853-4108T>C 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 152,060 control chromosomes in the GnomAD database, including 52,854 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 (52854 hom., cov: 31)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.788
• Publications: 18 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.853-4108T>C		intron_variant	Intron 3 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.853-4108T>C		intron_variant	Intron 3 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.-156-4108T>C		intron_variant	Intron 2 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.-156-4108T>C		intron_variant	Intron 2 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.853-4108T>C		intron_variant	Intron 3 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.853-4108T>C		intron_variant	Intron 2 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.853-4108T>C		intron_variant	Intron 3 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.833 AC: 126506 AN: 151940 Hom.: 52807 Cov.: 31

Gnomad AFR AF: 0.873

Gnomad AMI AF: 0.807

Gnomad AMR AF: 0.834

Gnomad ASJ AF: 0.849

Gnomad EAS AF: 0.801

Gnomad SAS AF: 0.851

Gnomad FIN AF: 0.801

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.813

Gnomad OTH AF: 0.829

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

GnomAD4 genome AF: 0.833 AC: 126611 AN: 152060 Hom.: 52854 Cov.: 31 AF XY: 0.832 AC XY: 61813 AN XY: 74314

African (AFR) AF: 0.873 AC: 36236 AN: 41494

American (AMR) AF: 0.833 AC: 12722 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.849 AC: 2943 AN: 3468

East Asian (EAS) AF: 0.801 AC: 4128 AN: 5152

South Asian (SAS) AF: 0.851 AC: 4088 AN: 4804

European-Finnish (FIN) AF: 0.801 AC: 8463 AN: 10568

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.813 AC: 55318 AN: 68006

Other (OTH) AF: 0.828 AC: 1738 AN: 2098

Alfa AF: 0.820 Hom.: 222619

Bravo AF: 0.838

Asia WGS AF: 0.802 AC: 2792 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Benign	0.77
PhyloP100		0.79
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: rs532967; hg19: chr12-117732339;