chr12-117247333-T-G

Variant names:

• chr12-117247333-T-G
• rs2291908
• NM_000620.5:c.2823+15A>C

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.2823+15A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,400,468 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: 𝑓 0.0 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.175
• 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: Variant has high frequency in the NFE (0.00202) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000620.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	NM_000620.5	MANE Select	c.2823+15A>C		intron	N/A	NP_000611.1
	NOS1	NM_001204218.2		c.2925+15A>C		intron	N/A	NP_001191147.1
	NOS1	NM_001204213.2		c.1815+15A>C		intron	N/A	NP_001191142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS1	ENST00000317775.11	TSL:1 MANE Select	c.2823+15A>C		intron	N/A	ENSP00000320758.6
	NOS1	ENST00000338101.8	TSL:5	c.2925+15A>C		intron	N/A	ENSP00000337459.4
	NOS1	ENST00000618760.4	TSL:5	c.2925+15A>C		intron	N/A	ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151522 Hom.: 0 Cov.: 30

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: 0.00180 AC: 2517 AN: 1400468 Hom.: 0 Cov.: 29 AF XY: 0.00163 AC XY: 1131 AN XY: 694698

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

African (AFR) AF: 0.00185 AC: 58 AN: 31268

American (AMR) AF: 0.000105 AC: 4 AN: 38224

Ashkenazi Jewish (ASJ) AF: 0.00104 AC: 25 AN: 23942

East Asian (EAS) AF: 0.000421 AC: 16 AN: 38006

South Asian (SAS) AF: 0.000610 AC: 49 AN: 80284

European-Finnish (FIN) AF: 0.000574 AC: 30 AN: 52294

Middle Eastern (MID) AF: 0.000725 AC: 4 AN: 5516

European-Non Finnish (NFE) AF: 0.00210 AC: 2249 AN: 1073004

Other (OTH) AF: 0.00142 AC: 82 AN: 57930

⚠️ 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 Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 151640 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74090

African (AFR) AF: 0.00 AC: 0 AN: 41358

American (AMR) AF: 0.00 AC: 0 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67872

Other (OTH) AF: 0.00 AC: 0 AN: 2098

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.8
DANN	Benign	0.74
PhyloP100		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2291908; hg19: chr12-117685138;