chr12-117220227-C-T

Variant names:

• chr12-117220227-C-T
• rs76104785
• NM_000620.5:c.4018G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000620.5(NOS1):​c.4018G>A​(p.Val1340Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,460,320 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (1 hom.)
• Consequence: NOS1 NM_000620.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.13
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000620.5. 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.4018G>A	p.Val1340Met	missense	Exon 27 of 29	NP_000611.1	P29475-1
	NOS1	NM_001204218.2		c.4120G>A	p.Val1374Met	missense	Exon 28 of 30	NP_001191147.1	P29475-5
	NOS1	NM_001204213.2		c.3010G>A	p.Val1004Met	missense	Exon 26 of 28	NP_001191142.1	P29475-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.4018G>A	p.Val1340Met	missense	Exon 27 of 29	ENSP00000320758.6	P29475-1
	NOS1	ENST00000338101.8	TSL:5	c.4120G>A	p.Val1374Met	missense	Exon 27 of 29	ENSP00000337459.4	P29475-5
	NOS1	ENST00000618760.4	TSL:5	c.4120G>A	p.Val1374Met	missense	Exon 28 of 30	ENSP00000477999.1	P29475-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248180 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

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: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460320 Hom.: 1 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726538

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.000179 AC: 8 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111760

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	0.0061	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.94	P
Vest4		0.57
MutPred		0.51		Gain of catalytic residue at L1336 (P = 2e-04)
MVP		0.88
MPC		1.4
ClinPred		0.93	D
GERP RS		3.5
Varity_R		0.17
gMVP		0.76
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76104785; hg19: chr12-117658032;