7-151002383-AACACACACACACACACACACACACACACACACACACACACACACAC-AACACACACACACACACACACACACACACACAC

Variant names:

• chr7-151002383-AACACACACACACAC-A
• rs3138808
• NM_000603.5:c.1752+136_1752+149delACACACACACACAC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000603.5(NOS3):​c.1752+136_1752+149delACACACACACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 270,760 control chromosomes in the GnomAD database, including 48 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.027 (46 hom., cov: 0)
  • Exomes 𝑓: 0.0071 (2 hom.)
• Consequence: NOS3 NM_000603.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.908
• Publications: 9 publications found

Genes affected

NOS3 (HGNC:7876): (nitric oxide synthase 3) Nitric oxide is a reactive free radical which acts as a biologic mediator in several processes, including neurotransmission and antimicrobial and antitumoral activities. Nitric oxide is synthesized from L-arginine by nitric oxide synthases. Variations in this gene are associated with susceptibility to coronary spasm. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0273 (1783/65236) while in subpopulation AFR AF = 0.0424 (750/17670). AF 95% confidence interval is 0.0399. There are 46 homozygotes in GnomAd4. There are 812 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1783 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000603.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS3	NM_000603.5	MANE Select	c.1752+136_1752+149delACACACACACACAC		intron	N/A	NP_000594.2
	NOS3	NM_001160111.1		c.1752+136_1752+149delACACACACACACAC		intron	N/A	NP_001153583.1	P29474-2
	NOS3	NM_001160110.1		c.1752+136_1752+149delACACACACACACAC		intron	N/A	NP_001153582.1	P29474-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS3	ENST00000297494.8	TSL:1 MANE Select	c.1752+80_1752+93delACACACACACACAC		intron	N/A	ENSP00000297494.3	P29474-1
	NOS3	ENST00000484524.5	TSL:1	c.1752+80_1752+93delACACACACACACAC		intron	N/A	ENSP00000420215.1	P29474-2
	NOS3	ENST00000467517.1	TSL:1	c.1752+80_1752+93delACACACACACACAC		intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 1780 AN: 65178 Hom.: 45 Cov.: 0

Gnomad AFR AF: 0.0423

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.0389

Gnomad SAS AF: 0.0399

Gnomad FIN AF: 0.0390

Gnomad MID AF: 0.0286

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.0396

GnomAD4 exome AF: 0.00708 AC: 1456 AN: 205524 Hom.: 2 AF XY: 0.00731 AC XY: 832 AN XY: 113770

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

African (AFR) AF: 0.00571 AC: 39 AN: 6828

American (AMR) AF: 0.00231 AC: 44 AN: 19010

Ashkenazi Jewish (ASJ) AF: 0.00627 AC: 43 AN: 6856

East Asian (EAS) AF: 0.00655 AC: 49 AN: 7484

South Asian (SAS) AF: 0.0103 AC: 396 AN: 38534

European-Finnish (FIN) AF: 0.0102 AC: 100 AN: 9802

Middle Eastern (MID) AF: 0.0119 AC: 10 AN: 842

European-Non Finnish (NFE) AF: 0.00674 AC: 715 AN: 106032

Other (OTH) AF: 0.00592 AC: 60 AN: 10136

⚠️ 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 AF: 0.0273 AC: 1783 AN: 65236 Hom.: 46 Cov.: 0 AF XY: 0.0270 AC XY: 812 AN XY: 30056

African (AFR) AF: 0.0424 AC: 750 AN: 17670

American (AMR) AF: 0.0199 AC: 111 AN: 5582

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 63 AN: 2004

East Asian (EAS) AF: 0.0390 AC: 90 AN: 2310

South Asian (SAS) AF: 0.0383 AC: 60 AN: 1566

European-Finnish (FIN) AF: 0.0390 AC: 108 AN: 2770

Middle Eastern (MID) AF: 0.0303 AC: 4 AN: 132

European-Non Finnish (NFE) AF: 0.0176 AC: 562 AN: 31900

Other (OTH) AF: 0.0403 AC: 35 AN: 868

Alfa AF: 0.00 Hom.: 86

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.91
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3138808; hg19: chr7-150699471;