7-151002383-AACACACACACACACACACACACACACACACACACACACACACACAC-AACACACACACACACACACAC

Variant names:

• chr7-151002383-AACACACACACACACACACACACACAC-A
• rs3138808
• NM_000603.5:c.1752+124_1752+149delACACACACACACACACACACACACAC

Variant summary

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

The NM_000603.5(NOS3):​c.1752+124_1752+149delACACACACACACACACACACACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00971 in 270,868 control chromosomes in the GnomAD database, including 30 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 0.022 (24 hom., cov: 0)
  • Exomes 𝑓: 0.0057 (6 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 sas. GnomAd4 allele frequency = 0.0225 (1467/65266) while in subpopulation SAS AF = 0.053 (83/1566). AF 95% confidence interval is 0.0438. There are 24 homozygotes in GnomAd4. There are 707 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1467 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+124_1752+149delACACACACACACACACACACACACAC		intron	N/A	NP_000594.2
	NOS3	NM_001160111.1		c.1752+124_1752+149delACACACACACACACACACACACACAC		intron	N/A	NP_001153583.1	P29474-2
	NOS3	NM_001160110.1		c.1752+124_1752+149delACACACACACACACACACACACACAC		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+105delACACACACACACACACACACACACAC		intron	N/A	ENSP00000297494.3	P29474-1
	NOS3	ENST00000484524.5	TSL:1	c.1752+80_1752+105delACACACACACACACACACACACACAC		intron	N/A	ENSP00000420215.1	P29474-2
	NOS3	ENST00000467517.1	TSL:1	c.1752+80_1752+105delACACACACACACACACACACACACAC		intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 1466 AN: 65208 Hom.: 24 Cov.: 0

Gnomad AFR AF: 0.0361

Gnomad AMI AF: 0.0115

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.00820

Gnomad SAS AF: 0.0525

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0163

GnomAD4 exome AF: 0.00566 AC: 1163 AN: 205602 Hom.: 6 AF XY: 0.00603 AC XY: 686 AN XY: 113828

African (AFR) AF: 0.00674 AC: 46 AN: 6828

American (AMR) AF: 0.000999 AC: 19 AN: 19012

Ashkenazi Jewish (ASJ) AF: 0.00802 AC: 55 AN: 6854

East Asian (EAS) AF: 0.00828 AC: 62 AN: 7490

South Asian (SAS) AF: 0.00968 AC: 373 AN: 38538

European-Finnish (FIN) AF: 0.00336 AC: 33 AN: 9814

Middle Eastern (MID) AF: 0.00119 AC: 1 AN: 842

European-Non Finnish (NFE) AF: 0.00495 AC: 525 AN: 106090

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

GnomAD4 genome AF: 0.0225 AC: 1467 AN: 65266 Hom.: 24 Cov.: 0 AF XY: 0.0235 AC XY: 707 AN XY: 30072

African (AFR) AF: 0.0360 AC: 637 AN: 17684

American (AMR) AF: 0.0154 AC: 86 AN: 5584

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

East Asian (EAS) AF: 0.00779 AC: 18 AN: 2310

South Asian (SAS) AF: 0.0530 AC: 83 AN: 1566

European-Finnish (FIN) AF: 0.0108 AC: 30 AN: 2778

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

European-Non Finnish (NFE) AF: 0.0166 AC: 531 AN: 31906

Other (OTH) AF: 0.0161 AC: 14 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;