chr12-117249694-A-G

Variant names:

• chr12-117249694-A-G
• rs816351
• NM_000620.5:c.2649-2172T>C

Variant summary

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

The NM_000620.5(NOS1):​c.2649-2172T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 152,066 control chromosomes in the GnomAD database, including 1,082 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 0.11 (1082 hom., cov: 31)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.535
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000620.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	NM_000620.5	MANE Select	c.2649-2172T>C		intron	N/A	NP_000611.1
	NOS1	NM_001204218.2		c.2751-2172T>C		intron	N/A	NP_001191147.1
	NOS1	NM_001204213.2		c.1641-2172T>C		intron	N/A	NP_001191142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.2649-2172T>C		intron	N/A	ENSP00000320758.6
	NOS1	ENST00000338101.8	TSL:5	c.2751-2172T>C		intron	N/A	ENSP00000337459.4
	NOS1	ENST00000618760.4	TSL:5	c.2751-2172T>C		intron	N/A	ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17193 AN: 151948 Hom.: 1079 Cov.: 31

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0798

Gnomad ASJ AF: 0.0646

Gnomad EAS AF: 0.0791

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0954

Gnomad OTH AF: 0.102

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

GnomAD4 genome AF: 0.113 AC: 17212 AN: 152066 Hom.: 1082 Cov.: 31 AF XY: 0.115 AC XY: 8517 AN XY: 74332

African (AFR) AF: 0.156 AC: 6457 AN: 41442

American (AMR) AF: 0.0796 AC: 1216 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0646 AC: 224 AN: 3470

East Asian (EAS) AF: 0.0793 AC: 410 AN: 5172

South Asian (SAS) AF: 0.138 AC: 661 AN: 4804

European-Finnish (FIN) AF: 0.139 AC: 1474 AN: 10588

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0954 AC: 6484 AN: 67994

Other (OTH) AF: 0.0995 AC: 210 AN: 2110

Alfa AF: 0.103 Hom.: 118

Bravo AF: 0.111

Asia WGS AF: 0.0910 AC: 315 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	10
DANN	Benign	0.59
PhyloP100		0.54
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: rs816351; hg19: chr12-117687499;