chr12-117215323-C-A

Variant names:

• chr12-117215323-C-A
• rs773164536
• NM_000620.5:c.4291G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000620.5(NOS1):​c.4291G>T​(p.Val1431Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000717 in 1,394,736 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1431I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: NOS1 NM_000620.5 missense, splice_region
• Scores: Splicing: ADA: 0.9711
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.89
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.4291G>T	p.Val1431Phe	missense_variant, splice_region_variant	Exon 29 of 29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.4393G>T	p.Val1465Phe	missense_variant, splice_region_variant	Exon 30 of 30		NP_001191147.1
NOS1	NM_001204213.2	c.3283G>T	p.Val1095Phe	missense_variant, splice_region_variant	Exon 28 of 28		NP_001191142.1
NOS1	NM_001204214.2	c.3283G>T	p.Val1095Phe	missense_variant, splice_region_variant	Exon 28 of 28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.4291G>T	p.Val1431Phe	missense_variant, splice_region_variant	Exon 29 of 29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.4393G>T	p.Val1465Phe	missense_variant, splice_region_variant	Exon 29 of 29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.4393G>T	p.Val1465Phe	missense_variant, splice_region_variant	Exon 30 of 30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394736 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 692282

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30866

American (AMR) AF: 0.00 AC: 0 AN: 36660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23808

East Asian (EAS) AF: 0.00 AC: 0 AN: 37110

South Asian (SAS) AF: 0.00 AC: 0 AN: 75420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5430

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076812

Other (OTH) AF: 0.00 AC: 0 AN: 57082

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T;.;T
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	M;.;.;.
PhyloP100		4.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.1	N;.;N;.
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.96	D;.;.;.
Vest4		0.59
MutPred		0.17		Gain of catalytic residue at V1431 (P = 0.0819);.;.;.;
MVP		0.37
MPC		1.4
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.58
gMVP		0.52
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.040		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: rs773164536; hg19: chr12-117653128;