7-151002383-AACACACACACACACACACACACACACACACACACACACACACACAC-AACACACACACACACACACACACACACAC

Variant names:

• chr7-151002383-AACACACACACACACACAC-A
• rs3138808
• NM_000603.5:c.1752+132_1752+149delACACACACACACACACAC

Variant summary

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

The NM_000603.5(NOS3):​c.1752+132_1752+149delACACACACACACACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 270,752 control chromosomes in the GnomAD database, including 149 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 0.055 (142 hom., cov: 0)
  • Exomes 𝑓: 0.0076 (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 (AFR) allele frequency at 95% confidence interval = 0.0956 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+132_1752+149delACACACACACACACACAC		intron	N/A	NP_000594.2
	NOS3	NM_001160111.1		c.1752+132_1752+149delACACACACACACACACAC		intron	N/A	NP_001153583.1	P29474-2
	NOS3	NM_001160110.1		c.1752+132_1752+149delACACACACACACACACAC		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+97delACACACACACACACACAC		intron	N/A	ENSP00000297494.3	P29474-1
	NOS3	ENST00000484524.5	TSL:1	c.1752+80_1752+97delACACACACACACACACAC		intron	N/A	ENSP00000420215.1	P29474-2
	NOS3	ENST00000467517.1	TSL:1	c.1752+80_1752+97delACACACACACACACACAC		intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes AF: 0.0546 AC: 3561 AN: 65170 Hom.: 143 Cov.: 0

Gnomad AFR AF: 0.0995

Gnomad AMI AF: 0.0787

Gnomad AMR AF: 0.0334

Gnomad ASJ AF: 0.0862

Gnomad EAS AF: 0.0307

Gnomad SAS AF: 0.0374

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.0714

Gnomad NFE AF: 0.0365

Gnomad OTH AF: 0.0443

GnomAD4 exome AF: 0.00762 AC: 1566 AN: 205524 Hom.: 7 AF XY: 0.00810 AC XY: 921 AN XY: 113754

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

African (AFR) AF: 0.0130 AC: 89 AN: 6822

American (AMR) AF: 0.00184 AC: 35 AN: 19008

Ashkenazi Jewish (ASJ) AF: 0.00876 AC: 60 AN: 6852

East Asian (EAS) AF: 0.0170 AC: 127 AN: 7480

South Asian (SAS) AF: 0.0117 AC: 449 AN: 38516

European-Finnish (FIN) AF: 0.00663 AC: 65 AN: 9810

Middle Eastern (MID) AF: 0.00833 AC: 7 AN: 840

European-Non Finnish (NFE) AF: 0.00633 AC: 671 AN: 106064

Other (OTH) AF: 0.00622 AC: 63 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: 0.0546 AC: 3562 AN: 65228 Hom.: 142 Cov.: 0 AF XY: 0.0538 AC XY: 1616 AN XY: 30054

African (AFR) AF: 0.0994 AC: 1757 AN: 17668

American (AMR) AF: 0.0331 AC: 185 AN: 5582

Ashkenazi Jewish (ASJ) AF: 0.0862 AC: 173 AN: 2006

East Asian (EAS) AF: 0.0307 AC: 71 AN: 2310

South Asian (SAS) AF: 0.0384 AC: 60 AN: 1564

European-Finnish (FIN) AF: 0.0274 AC: 76 AN: 2778

Middle Eastern (MID) AF: 0.0606 AC: 8 AN: 132

European-Non Finnish (NFE) AF: 0.0364 AC: 1160 AN: 31888

Other (OTH) AF: 0.0438 AC: 38 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;