12-117309405-T-C

Variant names:

• chr12-117309405-T-C
• rs7298903
• NM_000620.5:c.852+2061A>G

Variant summary

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

The NM_001204214.2(NOS1):​c.-301A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 983,844 control chromosomes in the GnomAD database, including 8,483 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 0.14 (1637 hom., cov: 32)
  • Exomes 𝑓: 0.13 (6846 hom.)
• Consequence: NOS1 NM_001204214.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.539
• Publications: 12 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204214.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	NM_000620.5	MANE Select	c.852+2061A>G		intron	N/A	NP_000611.1
	NOS1	NM_001204214.2		c.-301A>G		5_prime_UTR	Exon 1 of 28	NP_001191143.1
	NOS1	NM_001204218.2		c.852+2061A>G		intron	N/A	NP_001191147.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.852+2061A>G		intron	N/A	ENSP00000320758.6
	NOS1	ENST00000338101.8	TSL:5	c.852+2061A>G		intron	N/A	ENSP00000337459.4
	NOS1	ENST00000618760.4	TSL:5	c.852+2061A>G		intron	N/A	ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20679 AN: 152020 Hom.: 1636 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.147

GnomAD4 exome AF: 0.126 AC: 104595 AN: 831706 Hom.: 6846 Cov.: 26 AF XY: 0.126 AC XY: 48407 AN XY: 384124

African (AFR) AF: 0.106 AC: 1665 AN: 15768

American (AMR) AF: 0.196 AC: 192 AN: 982

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 726 AN: 5144

East Asian (EAS) AF: 0.252 AC: 913 AN: 3616

South Asian (SAS) AF: 0.252 AC: 4133 AN: 16408

European-Finnish (FIN) AF: 0.109 AC: 30 AN: 276

Middle Eastern (MID) AF: 0.123 AC: 199 AN: 1614

European-Non Finnish (NFE) AF: 0.122 AC: 92720 AN: 760650

Other (OTH) AF: 0.147 AC: 4017 AN: 27248

GnomAD4 genome AF: 0.136 AC: 20692 AN: 152138 Hom.: 1637 Cov.: 32 AF XY: 0.140 AC XY: 10408 AN XY: 74376

African (AFR) AF: 0.112 AC: 4659 AN: 41520

American (AMR) AF: 0.192 AC: 2934 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 475 AN: 3466

East Asian (EAS) AF: 0.264 AC: 1362 AN: 5154

South Asian (SAS) AF: 0.251 AC: 1210 AN: 4818

European-Finnish (FIN) AF: 0.112 AC: 1183 AN: 10590

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8492 AN: 68002

Other (OTH) AF: 0.146 AC: 307 AN: 2108

Alfa AF: 0.121 Hom.: 1004

Bravo AF: 0.137

Asia WGS AF: 0.230 AC: 799 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.43
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: rs7298903; hg19: chr12-117747210;