12-117218073-A-G

Variant names:

• chr12-117218073-A-G
• rs1448627745
• NM_000620.5:c.4262T>C

Variant summary

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

The NM_000620.5(NOS1):​c.4262T>C​(p.Ile1421Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NOS1 NM_000620.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.70
• Publications: 0 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.4262T>C	p.Ile1421Thr	missense_variant	Exon 28 of 29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.4364T>C	p.Ile1455Thr	missense_variant	Exon 29 of 30		NP_001191147.1
NOS1	NM_001204213.2	c.3254T>C	p.Ile1085Thr	missense_variant	Exon 27 of 28		NP_001191142.1
NOS1	NM_001204214.2	c.3254T>C	p.Ile1085Thr	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.4262T>C	p.Ile1421Thr	missense_variant	Exon 28 of 29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.4364T>C	p.Ile1455Thr	missense_variant	Exon 28 of 29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.4364T>C	p.Ile1455Thr	missense_variant	Exon 29 of 30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000802 AC: 2 AN: 249496 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461794 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4364T>C (p.I1455T) alteration is located in exon 29 (coding exon 28) of the NOS1 gene. This alteration results from a T to C substitution at nucleotide position 4364, causing the isoleucine (I) at amino acid position 1455 to be replaced by a threonine (T). 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	Benign	0.24
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;.;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.3	M;.;.;.
PhyloP100		8.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.94	N;.;N;.
REVEL	Uncertain	0.45
Sift	Benign	0.064	T;.;T;.
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.86	P;.;.;.
Vest4		0.81
MutPred		0.45		Loss of helix (P = 0.0237);.;.;.;
MVP		0.63
MPC		1.6
ClinPred		0.84	D
GERP RS		4.7
Varity_R		0.20
gMVP		0.71
Mutation Taster		=47/53	disease causing

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: rs1448627745; hg19: chr12-117655878;