12-117218101-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000620.5(NOS1):c.4234C>T(p.Arg1412Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,868 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NOS1
NM_000620.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.23

Publications

2 publications found

Variant links:

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

NOS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5 link	c.4234C>T	p.Arg1412Cys	missense_variant	Exon 28 of 29	ENST00000317775.11	NP_000611.1	P29475-1B3VK56A0PJJ7B4DG68
NOS1	NM_001204218.2 link	c.4336C>T	p.Arg1446Cys	missense_variant	Exon 29 of 30		NP_001191147.1	P29475-5A0PJJ7B4DG68
NOS1	NM_001204213.2 link	c.3226C>T	p.Arg1076Cys	missense_variant	Exon 27 of 28		NP_001191142.1	P29475-3A0PJJ7B4DG68
NOS1	NM_001204214.2 link	c.3226C>T	p.Arg1076Cys	missense_variant	Exon 27 of 28		NP_001191143.1	P29475-3A0PJJ7B4DG68

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOS1	ENST00000317775.11 link	c.4234C>T	p.Arg1412Cys	missense_variant	Exon 28 of 29	1	NM_000620.5	ENSP00000320758.6	P29475-1
NOS1	ENST00000338101.8 link	c.4336C>T	p.Arg1446Cys	missense_variant	Exon 28 of 29	5		ENSP00000337459.4	P29475-5
NOS1	ENST00000618760.4 link	c.4336C>T	p.Arg1446Cys	missense_variant	Exon 29 of 30	5		ENSP00000477999.1	P29475-5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152146

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74324

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 05, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4336C>T (p.R1446C) alteration is located in exon 29 (coding exon 28) of the NOS1 gene. This alteration results from a C to T substitution at nucleotide position 4336, causing the arginine (R) at amino acid position 1446 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

D;.;.;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;.;D

M_CAP

Benign

0.031

MetaRNN

Pathogenic

0.79

D;D;D;D

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.8

M;.;.;.

PhyloP100

5.2

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-4.9

D;.;D;.

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

D;.;D;.

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.80

MutPred

0.46

Gain of catalytic residue at L1413 (P = 0);.;.;.;

MVP

0.71

MPC

1.7

ClinPred

1.0

GERP RS

4.7

Varity_R

0.65

gMVP

0.82

Mutation Taster

=25/75

disease causing

(source)

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

Publications

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12-117218101-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over