NM_000620.5:c.3588T>C

Variant names:

• chr12-117227459-A-G
• rs9658501
• NM_000620.5:c.3588T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000620.5(NOS1):​c.3588T>C​(p.Thr1196Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,613,806 control chromosomes in the GnomAD database, including 274 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 (50 hom., cov: 32)
  • Exomes 𝑓: 0.012 (224 hom.)
• Consequence: NOS1 NM_000620.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP7: Synonymous conserved (PhyloP=-1.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.3588T>C	p.Thr1196Thr	synonymous_variant	Exon 23 of 29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.3690T>C	p.Thr1230Thr	synonymous_variant	Exon 24 of 30		NP_001191147.1
NOS1	NM_001204213.2	c.2580T>C	p.Thr860Thr	synonymous_variant	Exon 22 of 28		NP_001191142.1
NOS1	NM_001204214.2	c.2580T>C	p.Thr860Thr	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.3588T>C	p.Thr1196Thr	synonymous_variant	Exon 23 of 29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.3690T>C	p.Thr1230Thr	synonymous_variant	Exon 23 of 29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.3690T>C	p.Thr1230Thr	synonymous_variant	Exon 24 of 30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2878 AN: 152142 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0403

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.0576

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.00870

Gnomad OTH AF: 0.0272

GnomAD2 exomes AF: 0.0138 AC: 3431 AN: 248846 AF XY: 0.0131

Gnomad AFR exome AF: 0.0428

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.00569

Gnomad EAS exome AF: 0.0536

Gnomad FIN exome AF: 0.00251

Gnomad NFE exome AF: 0.00888

Gnomad OTH exome AF: 0.0128

GnomAD4 exome AF: 0.0120 AC: 17534 AN: 1461546 Hom.: 224 Cov.: 32 AF XY: 0.0118 AC XY: 8600 AN XY: 727028

African (AFR) AF: 0.0478 AC: 1601 AN: 33476

American (AMR) AF: 0.0119 AC: 531 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00502 AC: 131 AN: 26106

East Asian (EAS) AF: 0.0753 AC: 2988 AN: 39698

South Asian (SAS) AF: 0.00741 AC: 638 AN: 86156

European-Finnish (FIN) AF: 0.00189 AC: 101 AN: 53400

Middle Eastern (MID) AF: 0.0380 AC: 219 AN: 5758

European-Non Finnish (NFE) AF: 0.00929 AC: 10327 AN: 1111922

Other (OTH) AF: 0.0165 AC: 998 AN: 60384

GnomAD4 genome AF: 0.0189 AC: 2883 AN: 152260 Hom.: 50 Cov.: 32 AF XY: 0.0186 AC XY: 1383 AN XY: 74456

African (AFR) AF: 0.0404 AC: 1677 AN: 41548

American (AMR) AF: 0.0115 AC: 176 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.0575 AC: 297 AN: 5164

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4828

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10622

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.00870 AC: 592 AN: 68014

Other (OTH) AF: 0.0265 AC: 56 AN: 2116

Alfa AF: 0.0127 Hom.: 23

Bravo AF: 0.0212

Asia WGS AF: 0.0290 AC: 99 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0121

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.1
DANN	Benign	0.59
PhyloP100		-1.3
Mutation Taster		=89/11	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: rs9658501; hg19: chr12-117665264; COSMIC: COSV57618388;