NM_000603.5:c.1752+138_1752+149delACACACACACAC

Variant names:

• chr7-151002383-AACACACACACAC-A
• rs3138808
• NM_000603.5:c.1752+138_1752+149delACACACACACAC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000603.5(NOS3):​c.1752+138_1752+149delACACACACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0243 in 270,622 control chromosomes in the GnomAD database, including 181 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. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.070 (169 hom., cov: 0)
  • Exomes 𝑓: 0.0099 (12 hom.)
• Consequence: NOS3 NM_000603.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 7-151002383-AACACACACACAC-A is Benign according to our data. Variant chr7-151002383-AACACACACACAC-A is described in ClinVar as Benign. ClinVar VariationId is 1275619.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0797 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+138_1752+149delACACACACACAC		intron	N/A	NP_000594.2
	NOS3	NM_001160111.1		c.1752+138_1752+149delACACACACACAC		intron	N/A	NP_001153583.1	P29474-2
	NOS3	NM_001160110.1		c.1752+138_1752+149delACACACACACAC		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+91delACACACACACAC		intron	N/A	ENSP00000297494.3	P29474-1
	NOS3	ENST00000484524.5	TSL:1	c.1752+80_1752+91delACACACACACAC		intron	N/A	ENSP00000420215.1	P29474-2
	NOS3	ENST00000467517.1	TSL:1	c.1752+80_1752+91delACACACACACAC		intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 4527 AN: 65112 Hom.: 170 Cov.: 0

Gnomad AFR AF: 0.0684

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.0675

Gnomad ASJ AF: 0.0758

Gnomad EAS AF: 0.0341

Gnomad SAS AF: 0.0911

Gnomad FIN AF: 0.0794

Gnomad MID AF: 0.0643

Gnomad NFE AF: 0.0691

Gnomad OTH AF: 0.0548

GnomAD4 exome AF: 0.00993 AC: 2041 AN: 205452 Hom.: 12 AF XY: 0.0101 AC XY: 1151 AN XY: 113734

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

African (AFR) AF: 0.00660 AC: 45 AN: 6822

American (AMR) AF: 0.00258 AC: 49 AN: 18992

Ashkenazi Jewish (ASJ) AF: 0.00758 AC: 52 AN: 6858

East Asian (EAS) AF: 0.00695 AC: 52 AN: 7486

South Asian (SAS) AF: 0.0118 AC: 454 AN: 38528

European-Finnish (FIN) AF: 0.0145 AC: 142 AN: 9806

Middle Eastern (MID) AF: 0.0190 AC: 16 AN: 842

European-Non Finnish (NFE) AF: 0.0107 AC: 1136 AN: 105996

Other (OTH) AF: 0.00939 AC: 95 AN: 10122

⚠️ 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: 0.0695 AC: 4531 AN: 65170 Hom.: 169 Cov.: 0 AF XY: 0.0682 AC XY: 2046 AN XY: 30020

African (AFR) AF: 0.0685 AC: 1209 AN: 17658

American (AMR) AF: 0.0672 AC: 375 AN: 5578

Ashkenazi Jewish (ASJ) AF: 0.0758 AC: 152 AN: 2004

East Asian (EAS) AF: 0.0342 AC: 79 AN: 2310

South Asian (SAS) AF: 0.0920 AC: 144 AN: 1566

European-Finnish (FIN) AF: 0.0794 AC: 220 AN: 2772

Middle Eastern (MID) AF: 0.0682 AC: 9 AN: 132

European-Non Finnish (NFE) AF: 0.0691 AC: 2200 AN: 31848

Other (OTH) AF: 0.0541 AC: 47 AN: 868

Alfa AF: 0.0199 Hom.: 86

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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;