7-151002383-AACACACACACACACACACACACACACACACACACACACACACACAC-AACACACACACACACACACACAC

Variant names:

• chr7-151002383-AACACACACACACACACACACACAC-A
• rs3138808
• NM_000603.5:c.1752+126_1752+149delACACACACACACACACACACACAC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000603.5(NOS3):​c.1752+126_1752+149delACACACACACACACACACACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00532 in 270,876 control chromosomes in the GnomAD database, including 4 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 0.0050 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0054 (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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 324 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+126_1752+149delACACACACACACACACACACACAC		intron	N/A	NP_000594.2
	NOS3	NM_001160111.1		c.1752+126_1752+149delACACACACACACACACACACACAC		intron	N/A	NP_001153583.1	P29474-2
	NOS3	NM_001160110.1		c.1752+126_1752+149delACACACACACACACACACACACAC		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+103delACACACACACACACACACACACAC		intron	N/A	ENSP00000297494.3	P29474-1
	NOS3	ENST00000484524.5	TSL:1	c.1752+80_1752+103delACACACACACACACACACACACAC		intron	N/A	ENSP00000420215.1	P29474-2
	NOS3	ENST00000467517.1	TSL:1	c.1752+80_1752+103delACACACACACACACACACACACAC		intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes AF: 0.00498 AC: 325 AN: 65210 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00732

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.0204

Gnomad EAS AF: 0.00993

Gnomad SAS AF: 0.0190

Gnomad FIN AF: 0.00108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00241

Gnomad OTH AF: 0.00816

GnomAD4 exome AF: 0.00543 AC: 1116 AN: 205608 Hom.: 2 AF XY: 0.00546 AC XY: 622 AN XY: 113818

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

African (AFR) AF: 0.00644 AC: 44 AN: 6834

American (AMR) AF: 0.000842 AC: 16 AN: 19010

Ashkenazi Jewish (ASJ) AF: 0.00904 AC: 62 AN: 6858

East Asian (EAS) AF: 0.0164 AC: 123 AN: 7486

South Asian (SAS) AF: 0.00713 AC: 275 AN: 38544

European-Finnish (FIN) AF: 0.00377 AC: 37 AN: 9816

Middle Eastern (MID) AF: 0.00595 AC: 5 AN: 840

European-Non Finnish (NFE) AF: 0.00465 AC: 493 AN: 106088

Other (OTH) AF: 0.00602 AC: 61 AN: 10132

⚠️ 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: 0.00496 AC: 324 AN: 65268 Hom.: 2 Cov.: 0 AF XY: 0.00545 AC XY: 164 AN XY: 30072

African (AFR) AF: 0.00724 AC: 128 AN: 17686

American (AMR) AF: 0.00269 AC: 15 AN: 5584

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 41 AN: 2008

East Asian (EAS) AF: 0.00996 AC: 23 AN: 2310

South Asian (SAS) AF: 0.0192 AC: 30 AN: 1566

European-Finnish (FIN) AF: 0.00108 AC: 3 AN: 2778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 132

European-Non Finnish (NFE) AF: 0.00241 AC: 77 AN: 31902

Other (OTH) AF: 0.00806 AC: 7 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;