12-117218154-C-T

Variant names:

• chr12-117218154-C-T
• rs376113705
• NM_000620.5:c.4181G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000620.5(NOS1):​c.4181G>A​(p.Arg1394Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,613,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: NOS1 NM_000620.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.51
• Publications: 7 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 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.4181G>A	p.Arg1394Gln	missense_variant	Exon 28 of 29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.4283G>A	p.Arg1428Gln	missense_variant	Exon 29 of 30		NP_001191147.1
NOS1	NM_001204213.2	c.3173G>A	p.Arg1058Gln	missense_variant	Exon 27 of 28		NP_001191142.1
NOS1	NM_001204214.2	c.3173G>A	p.Arg1058Gln	missense_variant	Exon 27 of 28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.4181G>A	p.Arg1394Gln	missense_variant	Exon 28 of 29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.4283G>A	p.Arg1428Gln	missense_variant	Exon 28 of 29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.4283G>A	p.Arg1428Gln	missense_variant	Exon 29 of 30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000176 AC: 44 AN: 249422 AF XY: 0.000200

Gnomad AFR exome AF: 0.000194

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: 0.000221

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000162 AC: 237 AN: 1461038 Hom.: 0 Cov.: 30 AF XY: 0.000172 AC XY: 125 AN XY: 726888

African (AFR) AF: 0.0000598 AC: 2 AN: 33468

American (AMR) AF: 0.0000894 AC: 4 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.000184 AC: 205 AN: 1111264

Other (OTH) AF: 0.0000994 AC: 6 AN: 60382

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74434

African (AFR) AF: 0.0000963 AC: 4 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68000

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.000144

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000207 AC: 25

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Uncertain significance and reported on 05-29-2015 by GeneDx. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;.;.;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;.;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.4	M;.;.;.
PhyloP100		7.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.6	D;.;D;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.91
MVP		0.94
MPC		1.6
ClinPred		0.42	T
GERP RS		4.6
Varity_R		0.69
gMVP		0.92
Mutation Taster		=72/28	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: rs376113705; hg19: chr12-117655959; COSMIC: COSV57608923;