rs9658256

Variant names:

• chr12-117361744-G-A
• rs9658256
• ENST00000618760.4:c.-653C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The ENST00000618760.4(NOS1):​c.-653C>T variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0187 in 152,210 control chromosomes in the GnomAD database, including 36 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 0.019 (36 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NOS1 ENST00000618760.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.62
• Publications: 4 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=-0.36).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0187 (2842/152210) while in subpopulation AMR AF = 0.0284 (434/15302). AF 95% confidence interval is 0.0262. There are 36 homozygotes in GnomAd4. There are 1387 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.-653C>T		upstream_gene_variant		ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.-653C>T		upstream_gene_variant			NP_001191147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000618760.4	c.-653C>T		5_prime_UTR_variant	Exon 1 of 30	5		ENSP00000477999.1
NOS1	ENST00000549189.1	n.471-30255C>T		intron_variant	Intron 1 of 1	3
NOS1	ENST00000317775.11	c.-653C>T		upstream_gene_variant		1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000477584.1	n.-115C>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2841 AN: 152094 Hom.: 36 Cov.: 30

Gnomad AFR AF: 0.00492

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.0320

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0206

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 24 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 18

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 14

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0187 AC: 2842 AN: 152210 Hom.: 36 Cov.: 30 AF XY: 0.0186 AC XY: 1387 AN XY: 74406

African (AFR) AF: 0.00491 AC: 204 AN: 41548

American (AMR) AF: 0.0284 AC: 434 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5162

South Asian (SAS) AF: 0.00912 AC: 44 AN: 4822

European-Finnish (FIN) AF: 0.0320 AC: 339 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0253 AC: 1718 AN: 68006

Other (OTH) AF: 0.0204 AC: 43 AN: 2110

Alfa AF: 0.0200 Hom.: 3

Bravo AF: 0.0166

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Benign	0.94
PhyloP100		4.6
PromoterAI		0.11	Neutral
Mutation Taster		=287/13	polymorphism

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: rs9658256; hg19: chr12-117799549;