12-117227594-G-A

Variant names:

• chr12-117227594-G-A
• rs9658500
• NM_000620.5:c.3453C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000620.5(NOS1):​c.3453C>T​(p.Ile1151Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,614,064 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (11 hom.)
• Consequence: NOS1 NM_000620.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.742
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-117227594-G-A is Benign according to our data. Variant chr12-117227594-G-A is described in ClinVar as [Benign]. Clinvar id is 711575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.742 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00756 (1151/152300) while in subpopulation AFR AF = 0.0262 (1090/41548). AF 95% confidence interval is 0.0249. There are 14 homozygotes in GnomAd4. There are 540 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.3453C>T	p.Ile1151Ile	synonymous_variant	Exon 23 of 29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.3555C>T	p.Ile1185Ile	synonymous_variant	Exon 24 of 30		NP_001191147.1
NOS1	NM_001204213.2	c.2445C>T	p.Ile815Ile	synonymous_variant	Exon 22 of 28		NP_001191142.1
NOS1	NM_001204214.2	c.2445C>T	p.Ile815Ile	synonymous_variant	Exon 22 of 28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.3453C>T	p.Ile1151Ile	synonymous_variant	Exon 23 of 29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.3555C>T	p.Ile1185Ile	synonymous_variant	Exon 23 of 29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.3555C>T	p.Ile1185Ile	synonymous_variant	Exon 24 of 30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.00757 AC: 1152 AN: 152182 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00193 AC: 481 AN: 249182 AF XY: 0.00151

Gnomad AFR exome AF: 0.0260

Gnomad AMR exome AF: 0.00183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000842 AC: 1231 AN: 1461764 Hom.: 11 Cov.: 32 AF XY: 0.000773 AC XY: 562 AN XY: 727170

African (AFR) AF: 0.0287 AC: 962 AN: 33476

American (AMR) AF: 0.00188 AC: 84 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111938

Other (OTH) AF: 0.00210 AC: 127 AN: 60384

GnomAD4 genome AF: 0.00756 AC: 1151 AN: 152300 Hom.: 14 Cov.: 32 AF XY: 0.00725 AC XY: 540 AN XY: 74472

African (AFR) AF: 0.0262 AC: 1090 AN: 41548

American (AMR) AF: 0.00288 AC: 44 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

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

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00353 Hom.: 5

Bravo AF: 0.00855

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NOS1-related disorder Benign:1

Apr 04, 2024

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	-0.39
CADD	Benign	8.3
DANN	Benign	0.81
PhyloP100		-0.74
Mutation Taster		=92/8	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: rs9658500; hg19: chr12-117665399; COSMIC: COSV57610873;