NM_000603.5:c.1752+144_1752+149delACACAC

Variant names:

• chr7-151002383-AACACAC-A
• rs3138808
• NM_000603.5:c.1752+144_1752+149delACACAC

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+144_1752+149delACACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 270,716 control chromosomes in the GnomAD database, including 188 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.061 (184 hom., cov: 0)
  • Exomes 𝑓: 0.0053 (4 hom.)
• Consequence: NOS3 NM_000603.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.192
• 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-AACACAC-A is Benign according to our data. Variant chr7-151002383-AACACAC-A is described in ClinVar as Benign. ClinVar VariationId is 1261942.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0691 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+144_1752+149delACACAC		intron	N/A	NP_000594.2
	NOS3	NM_001160111.1		c.1752+144_1752+149delACACAC		intron	N/A	NP_001153583.1	P29474-2
	NOS3	NM_001160110.1		c.1752+144_1752+149delACACAC		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+85delACACAC		intron	N/A	ENSP00000297494.3	P29474-1
	NOS3	ENST00000484524.5	TSL:1	c.1752+80_1752+85delACACAC		intron	N/A	ENSP00000420215.1	P29474-2
	NOS3	ENST00000467517.1	TSL:1	c.1752+80_1752+85delACACAC		intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes AF: 0.0607 AC: 3946 AN: 65048 Hom.: 184 Cov.: 0

Gnomad AFR AF: 0.0394

Gnomad AMI AF: 0.0926

Gnomad AMR AF: 0.0709

Gnomad ASJ AF: 0.0623

Gnomad EAS AF: 0.0402

Gnomad SAS AF: 0.0425

Gnomad FIN AF: 0.0683

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.0715

Gnomad OTH AF: 0.0618

GnomAD4 exome AF: 0.00534 AC: 1097 AN: 205610 Hom.: 4 AF XY: 0.00545 AC XY: 621 AN XY: 113842

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

African (AFR) AF: 0.00264 AC: 18 AN: 6824

American (AMR) AF: 0.00200 AC: 38 AN: 19012

Ashkenazi Jewish (ASJ) AF: 0.00335 AC: 23 AN: 6860

East Asian (EAS) AF: 0.00388 AC: 29 AN: 7480

South Asian (SAS) AF: 0.00480 AC: 185 AN: 38578

European-Finnish (FIN) AF: 0.00713 AC: 70 AN: 9812

Middle Eastern (MID) AF: 0.00831 AC: 7 AN: 842

European-Non Finnish (NFE) AF: 0.00640 AC: 679 AN: 106070

Other (OTH) AF: 0.00474 AC: 48 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: 0.0607 AC: 3950 AN: 65106 Hom.: 184 Cov.: 0 AF XY: 0.0598 AC XY: 1794 AN XY: 30008

African (AFR) AF: 0.0395 AC: 697 AN: 17644

American (AMR) AF: 0.0708 AC: 394 AN: 5568

Ashkenazi Jewish (ASJ) AF: 0.0623 AC: 125 AN: 2006

East Asian (EAS) AF: 0.0399 AC: 92 AN: 2306

South Asian (SAS) AF: 0.0429 AC: 67 AN: 1562

European-Finnish (FIN) AF: 0.0683 AC: 189 AN: 2768

Middle Eastern (MID) AF: 0.121 AC: 16 AN: 132

European-Non Finnish (NFE) AF: 0.0715 AC: 2276 AN: 31820

Other (OTH) AF: 0.0622 AC: 54 AN: 868

Alfa AF: 0.00 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		0.19
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;