7-151002383-AACACACACACACACACACACACACACACACACACACACACACACAC-AACACACACACACACACACACACACAC

Variant names:

• chr7-151002383-AACACACACACACACACACAC-A
• rs3138808
• NM_000603.5:c.1752+130_1752+149delACACACACACACACACACAC

Variant summary

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

The NM_000603.5(NOS3):​c.1752+130_1752+149delACACACACACACACACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 270,812 control chromosomes in the GnomAD database, including 43 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 0.025 (36 hom., cov: 0)
  • Exomes 𝑓: 0.0079 (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.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0251 (1637/65266) while in subpopulation SAS AF = 0.0428 (67/1566). AF 95% confidence interval is 0.0346. There are 36 homozygotes in GnomAd4. There are 773 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1637 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+130_1752+149delACACACACACACACACACAC		intron	N/A	NP_000594.2
	NOS3	NM_001160111.1		c.1752+130_1752+149delACACACACACACACACACAC		intron	N/A	NP_001153583.1	P29474-2
	NOS3	NM_001160110.1		c.1752+130_1752+149delACACACACACACACACACAC		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+99delACACACACACACACACACAC		intron	N/A	ENSP00000297494.3	P29474-1
	NOS3	ENST00000484524.5	TSL:1	c.1752+80_1752+99delACACACACACACACACACAC		intron	N/A	ENSP00000420215.1	P29474-2
	NOS3	ENST00000467517.1	TSL:1	c.1752+80_1752+99delACACACACACACACACACAC		intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 1636 AN: 65208 Hom.: 36 Cov.: 0

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.0346

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0229

Gnomad EAS AF: 0.0268

Gnomad SAS AF: 0.0418

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0143

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0280

GnomAD4 exome AF: 0.00790 AC: 1623 AN: 205546 Hom.: 7 AF XY: 0.00827 AC XY: 941 AN XY: 113766

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

African (AFR) AF: 0.0101 AC: 69 AN: 6828

American (AMR) AF: 0.00126 AC: 24 AN: 19014

Ashkenazi Jewish (ASJ) AF: 0.00701 AC: 48 AN: 6852

East Asian (EAS) AF: 0.0134 AC: 100 AN: 7486

South Asian (SAS) AF: 0.0114 AC: 439 AN: 38518

European-Finnish (FIN) AF: 0.0194 AC: 190 AN: 9798

Middle Eastern (MID) AF: 0.00475 AC: 4 AN: 842

European-Non Finnish (NFE) AF: 0.00632 AC: 670 AN: 106076

Other (OTH) AF: 0.00780 AC: 79 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: 0.0251 AC: 1637 AN: 65266 Hom.: 36 Cov.: 0 AF XY: 0.0257 AC XY: 773 AN XY: 30072

African (AFR) AF: 0.0220 AC: 390 AN: 17688

American (AMR) AF: 0.0136 AC: 76 AN: 5582

Ashkenazi Jewish (ASJ) AF: 0.0229 AC: 46 AN: 2006

East Asian (EAS) AF: 0.0264 AC: 61 AN: 2310

South Asian (SAS) AF: 0.0428 AC: 67 AN: 1566

European-Finnish (FIN) AF: 0.107 AC: 297 AN: 2780

Middle Eastern (MID) AF: 0.0152 AC: 2 AN: 132

European-Non Finnish (NFE) AF: 0.0207 AC: 659 AN: 31900

Other (OTH) AF: 0.0276 AC: 24 AN: 868

Alfa AF: 0.0111 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;