7-151002383-AACACACACACACACACACACACACACACACACACACACACACACAC-AACACACACACACAC

Variant names:

• chr7-151002383-AACACACACACACACACACACACACACACACAC-A
• rs3138808
• NM_000603.5:c.1752+118_1752+149delACACACACACACACACACACACACACACACAC

Variant summary

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

The NM_000603.5(NOS3):​c.1752+118_1752+149delACACACACACACACACACACACACACACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 271,048 control chromosomes in the GnomAD database, including 26 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 0.015 (23 hom., cov: 0)
  • Exomes 𝑓: 0.0010 (3 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 = 0.015 (981/65262) while in subpopulation AFR AF = 0.0519 (918/17680). AF 95% confidence interval is 0.0491. There are 23 homozygotes in GnomAd4. There are 495 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 981 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS3	NM_000603.5	MANE Select	c.1752+118_1752+149delACACACACACACACACACACACACACACACAC		intron	N/A	NP_000594.2
	NOS3	NM_001160111.1		c.1752+118_1752+149delACACACACACACACACACACACACACACACAC		intron	N/A	NP_001153583.1
	NOS3	NM_001160110.1		c.1752+118_1752+149delACACACACACACACACACACACACACACACAC		intron	N/A	NP_001153582.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS3	ENST00000297494.8	TSL:1 MANE Select	c.1752+80_1752+111delACACACACACACACACACACACACACACACAC		intron	N/A	ENSP00000297494.3
	NOS3	ENST00000484524.5	TSL:1	c.1752+80_1752+111delACACACACACACACACACACACACACACACAC		intron	N/A	ENSP00000420215.1
	NOS3	ENST00000467517.1	TSL:1	c.1752+80_1752+111delACACACACACACACACACACACACACACACAC		intron	N/A	ENSP00000420551.1

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 985 AN: 65204 Hom.: 23 Cov.: 0

Gnomad AFR AF: 0.0524

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000864

Gnomad SAS AF: 0.00190

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00714

Gnomad NFE AF: 0.000282

Gnomad OTH AF: 0.0152

GnomAD4 exome AF: 0.00102 AC: 209 AN: 205786 Hom.: 3 AF XY: 0.000851 AC XY: 97 AN XY: 113938

African (AFR) AF: 0.0192 AC: 131 AN: 6818

American (AMR) AF: 0.000684 AC: 13 AN: 19014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6862

East Asian (EAS) AF: 0.00134 AC: 10 AN: 7488

South Asian (SAS) AF: 0.000207 AC: 8 AN: 38612

European-Finnish (FIN) AF: 0.000204 AC: 2 AN: 9820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 842

European-Non Finnish (NFE) AF: 0.000226 AC: 24 AN: 106186

Other (OTH) AF: 0.00207 AC: 21 AN: 10144

GnomAD4 genome AF: 0.0150 AC: 981 AN: 65262 Hom.: 23 Cov.: 0 AF XY: 0.0165 AC XY: 495 AN XY: 30070

African (AFR) AF: 0.0519 AC: 918 AN: 17680

American (AMR) AF: 0.00627 AC: 35 AN: 5584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2006

East Asian (EAS) AF: 0.000866 AC: 2 AN: 2310

South Asian (SAS) AF: 0.00192 AC: 3 AN: 1566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2778

Middle Eastern (MID) AF: 0.00758 AC: 1 AN: 132

European-Non Finnish (NFE) AF: 0.000282 AC: 9 AN: 31904

Other (OTH) AF: 0.0150 AC: 13 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		=98/2	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;