12-117226750-G-A

Position:

• chr12-117226750-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_000620.5(NOS1):​c.3637C>T​(p.His1213Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,461,692 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (1 hom.)
• Consequence: NOS1 NM_000620.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.00

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NOS1. . Gene score misZ 3.6832 (greater than the threshold 3.09). Trascript score misZ 4.7179 (greater than threshold 3.09). GenCC has associacion of gene with idiopathic achalasia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29839894).
• BS2: High AC in GnomAdExome4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS1	NM_000620.5	c.3637C>T	p.His1213Tyr	missense_variant	24/29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.3739C>T	p.His1247Tyr	missense_variant	25/30		NP_001191147.1
NOS1	NM_001204213.2	c.2629C>T	p.His877Tyr	missense_variant	23/28		NP_001191142.1
NOS1	NM_001204214.2	c.2629C>T	p.His877Tyr	missense_variant	23/28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.3637C>T	p.His1213Tyr	missense_variant	24/29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.3739C>T	p.His1247Tyr	missense_variant	24/29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.3739C>T	p.His1247Tyr	missense_variant	25/30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000401 AC: 10 AN: 249414 Hom.: 1 AF XY: 0.0000665 AC XY: 9 AN XY: 135314

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 SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461692 Hom.: 1 Cov.: 30 AF XY: 0.0000371 AC XY: 27 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2023

The c.3739C>T (p.H1247Y) alteration is located in exon 25 (coding exon 24) of the NOS1 gene. This alteration results from a C to T substitution at nucleotide position 3739, causing the histidine (H) at amino acid position 1247 to be replaced by a tyrosine (Y). 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	0.12
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D;.;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.0098
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;T;.;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.43	N;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.2	D;.;N;.
REVEL	Uncertain	0.30
Sift	Benign	0.81	T;.;T;.
Sift4G	Benign	0.67	T;T;T;T
Polyphen		0.014	B;.;.;.
Vest4		0.50
MutPred		0.47		Gain of catalytic residue at S1218 (P = 0);.;.;.;
MVP		0.86
MPC		0.77
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.30
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs766800474; hg19: chr12-117664555;