7-151002383-AACACACACACACACACACACACACACACACACACACACACACACAC-AACACACACACACACACACACACACACACAC

Variant names:

• chr7-151002383-AACACACACACACACAC-A
• rs3138808
• NM_000603.5:c.1752+134_1752+149delACACACACACACACAC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000603.5(NOS3):​c.1752+134_1752+149delACACACACACACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 270,796 control chromosomes in the GnomAD database, including 57 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 0.029 (50 hom., cov: 0)
  • Exomes 𝑓: 0.0065 (7 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.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

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+134_1752+149delACACACACACACACAC		intron	N/A	NP_000594.2
	NOS3	NM_001160111.1		c.1752+134_1752+149delACACACACACACACAC		intron	N/A	NP_001153583.1	P29474-2
	NOS3	NM_001160110.1		c.1752+134_1752+149delACACACACACACACAC		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+95delACACACACACACACAC		intron	N/A	ENSP00000297494.3	P29474-1
	NOS3	ENST00000484524.5	TSL:1	c.1752+80_1752+95delACACACACACACACAC		intron	N/A	ENSP00000420215.1	P29474-2
	NOS3	ENST00000467517.1	TSL:1	c.1752+80_1752+95delACACACACACACACAC		intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 1858 AN: 65184 Hom.: 49 Cov.: 0

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.0797

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.0214

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0420

GnomAD4 exome AF: 0.00647 AC: 1330 AN: 205554 Hom.: 7 AF XY: 0.00717 AC XY: 816 AN XY: 113778

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

African (AFR) AF: 0.00528 AC: 36 AN: 6822

American (AMR) AF: 0.00110 AC: 21 AN: 19014

Ashkenazi Jewish (ASJ) AF: 0.00437 AC: 30 AN: 6858

East Asian (EAS) AF: 0.0171 AC: 128 AN: 7486

South Asian (SAS) AF: 0.0128 AC: 494 AN: 38540

European-Finnish (FIN) AF: 0.00633 AC: 62 AN: 9802

Middle Eastern (MID) AF: 0.00716 AC: 6 AN: 838

European-Non Finnish (NFE) AF: 0.00475 AC: 504 AN: 106060

Other (OTH) AF: 0.00484 AC: 49 AN: 10134

⚠️ 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: 0.0286 AC: 1864 AN: 65242 Hom.: 50 Cov.: 0 AF XY: 0.0304 AC XY: 913 AN XY: 30068

African (AFR) AF: 0.0306 AC: 541 AN: 17680

American (AMR) AF: 0.0224 AC: 125 AN: 5586

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 44 AN: 2006

East Asian (EAS) AF: 0.115 AC: 266 AN: 2306

South Asian (SAS) AF: 0.0817 AC: 128 AN: 1566

European-Finnish (FIN) AF: 0.0159 AC: 44 AN: 2774

Middle Eastern (MID) AF: 0.0227 AC: 3 AN: 132

European-Non Finnish (NFE) AF: 0.0212 AC: 676 AN: 31890

Other (OTH) AF: 0.0426 AC: 37 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;