12-117277815-G-T

Variant names:

• chr12-117277815-G-T
• rs2293052
• NM_000620.5:c.1664+144C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000620.5(NOS1):​c.1664+144C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 800,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.1664+144C>A		intron_variant	Intron 9 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.1664+144C>A		intron_variant	Intron 9 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.656+144C>A		intron_variant	Intron 8 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.656+144C>A		intron_variant	Intron 8 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.1664+144C>A		intron_variant	Intron 9 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.1664+144C>A		intron_variant	Intron 8 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.1664+144C>A		intron_variant	Intron 9 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000125 AC: 1 AN: 800758 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 404506

⚠️ 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: 19262

American (AMR) AF: 0.00 AC: 0 AN: 22302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15008

East Asian (EAS) AF: 0.00 AC: 0 AN: 33506

South Asian (SAS) AF: 0.00 AC: 0 AN: 49190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2526

European-Non Finnish (NFE) AF: 0.00000171 AC: 1 AN: 584978

Other (OTH) AF: 0.00 AC: 0 AN: 36872

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.16
DANN	Benign	0.80
PhyloP100		-1.3

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: rs2293052; hg19: chr12-117715620;