12-117215301-G-A

Variant names:

• chr12-117215301-G-A
• rs9658557
• NM_000620.5:c.*8C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000620.5(NOS1):​c.*8C>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 0.000485 in 1,557,412 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (2 hom.)
• Consequence: NOS1 NM_000620.5 3_prime_UTR
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.05
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 12-117215301-G-A is Benign according to our data. Variant chr12-117215301-G-A is described in ClinVar as [Benign]. Clinvar id is 3033399.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.*8C>T		3_prime_UTR_variant	Exon 29 of 29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.*8C>T		3_prime_UTR_variant	Exon 30 of 30		NP_001191147.1
NOS1	NM_001204213.2	c.*8C>T		3_prime_UTR_variant	Exon 28 of 28		NP_001191142.1
NOS1	NM_001204214.2	c.*8C>T		3_prime_UTR_variant	Exon 28 of 28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.*8C>T		3_prime_UTR_variant	Exon 29 of 29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.*8C>T		3_prime_UTR_variant	Exon 29 of 29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.*8C>T		3_prime_UTR_variant	Exon 30 of 30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.00256 AC: 390 AN: 152206 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00900

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000677 AC: 149 AN: 220178 AF XY: 0.000565

Gnomad AFR exome AF: 0.00926

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000198

GnomAD4 exome AF: 0.000260 AC: 365 AN: 1405088 Hom.: 2 Cov.: 33 AF XY: 0.000199 AC XY: 139 AN XY: 697708

African (AFR) AF: 0.0103 AC: 321 AN: 31218

American (AMR) AF: 0.000558 AC: 21 AN: 37646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24270

East Asian (EAS) AF: 0.00 AC: 0 AN: 37476

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 77074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5494

European-Non Finnish (NFE) AF: 0.00000554 AC: 6 AN: 1082406

Other (OTH) AF: 0.000278 AC: 16 AN: 57646

GnomAD4 genome AF: 0.00256 AC: 390 AN: 152324 Hom.: 3 Cov.: 32 AF XY: 0.00246 AC XY: 183 AN XY: 74504

African (AFR) AF: 0.00897 AC: 373 AN: 41568

American (AMR) AF: 0.000915 AC: 14 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00190 Hom.: 1

Bravo AF: 0.00332

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

NOS1-related disorder Benign:1

Jun 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.86
PhyloP100		3.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs9658557; hg19: chr12-117653106;