12-117209598-G-A

Variant names:

• chr12-117209598-G-A
• rs10774907
• NM_000620.5:c.*5711C>T

Variant summary

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

The NM_000620.5(NOS1):​c.*5711C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 985,350 control chromosomes in the GnomAD database, including 58,381 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 0.46 (21045 hom., cov: 33)
  • Exomes 𝑓: 0.29 (37336 hom.)
• Consequence: NOS1 NM_000620.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.239
• Publications: 6 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.852 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.*5711C>T		3_prime_UTR	Exon 29 of 29	NP_000611.1
	NOS1	NM_001204218.2		c.*5711C>T		3_prime_UTR	Exon 30 of 30	NP_001191147.1
	NOS1	NM_001204213.2		c.*5711C>T		3_prime_UTR	Exon 28 of 28	NP_001191142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.*5711C>T		3_prime_UTR	Exon 29 of 29	ENSP00000320758.6
	NOS1	ENST00000618760.4	TSL:5	c.*5711C>T		3_prime_UTR	Exon 30 of 30	ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69333 AN: 152112 Hom.: 20980 Cov.: 33

Gnomad AFR AF: 0.859

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.484

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.389

GnomAD4 exome AF: 0.286 AC: 237931 AN: 833118 Hom.: 37336 Cov.: 31 AF XY: 0.284 AC XY: 109422 AN XY: 384722

African (AFR) AF: 0.905 AC: 14294 AN: 15786

American (AMR) AF: 0.420 AC: 413 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 889 AN: 5152

East Asian (EAS) AF: 0.492 AC: 1784 AN: 3628

South Asian (SAS) AF: 0.238 AC: 3920 AN: 16460

European-Finnish (FIN) AF: 0.308 AC: 85 AN: 276

Middle Eastern (MID) AF: 0.211 AC: 342 AN: 1622

European-Non Finnish (NFE) AF: 0.273 AC: 207972 AN: 761912

Other (OTH) AF: 0.302 AC: 8232 AN: 27298

GnomAD4 genome AF: 0.456 AC: 69461 AN: 152232 Hom.: 21045 Cov.: 33 AF XY: 0.452 AC XY: 33674 AN XY: 74434

African (AFR) AF: 0.859 AC: 35714 AN: 41570

American (AMR) AF: 0.471 AC: 7202 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 637 AN: 3468

East Asian (EAS) AF: 0.485 AC: 2510 AN: 5176

South Asian (SAS) AF: 0.245 AC: 1183 AN: 4830

European-Finnish (FIN) AF: 0.285 AC: 3022 AN: 10592

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 17992 AN: 67982

Other (OTH) AF: 0.392 AC: 828 AN: 2110

Alfa AF: 0.347 Hom.: 9985

Bravo AF: 0.493

Asia WGS AF: 0.401 AC: 1395 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.59
DANN	Benign	0.74
PhyloP100		-0.24
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: rs10774907; hg19: chr12-117647403;