rs17223045

Variant names:

• chr19-855587-C-T
• rs17223045
• NM_001972.4:c.390C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001972.4(ELANE):​c.390C>T​(p.Asn130Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,600,284 control chromosomes in the GnomAD database, including 372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (130 hom., cov: 32)
  • Exomes 𝑓: 0.013 (242 hom.)
• Consequence: ELANE NM_001972.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.34
• Publications: 7 publications found

Genes affected

ELANE (HGNC:3309): (elastase, neutrophil expressed) Elastases form a subfamily of serine proteases that hydrolyze many proteins in addition to elastin. Humans have six elastase genes which encode structurally similar proteins. The encoded preproprotein is proteolytically processed to generate the active protease. Following activation, this protease hydrolyzes proteins within specialized neutrophil lysosomes, called azurophil granules, as well as proteins of the extracellular matrix. The enzyme may play a role in degenerative and inflammatory diseases through proteolysis of collagen-IV and elastin. This protein also degrades the outer membrane protein A (OmpA) of E. coli as well as the virulence factors of such bacteria as Shigella, Salmonella and Yersinia. Mutations in this gene are associated with cyclic neutropenia and severe congenital neutropenia (SCN). This gene is present in a gene cluster on chromosome 19. [provided by RefSeq, Jan 2016]

ELANE Gene-Disease associations (from GenCC):

• neutropenia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• cyclic hematopoiesis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant severe congenital neutropenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 19-855587-C-T is Benign according to our data. Variant chr19-855587-C-T is described in ClinVar as Benign. ClinVar VariationId is 258498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.069 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001972.4. 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
	ELANE	NM_001972.4	MANE Select	c.390C>T	p.Asn130Asn	synonymous	Exon 4 of 5	NP_001963.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELANE	ENST00000263621.2	TSL:1 MANE Select	c.390C>T	p.Asn130Asn	synonymous	Exon 4 of 5	ENSP00000263621.1
	ELANE	ENST00000590230.5	TSL:5	c.390C>T	p.Asn130Asn	synonymous	Exon 5 of 6	ENSP00000466090.1

Frequencies

GnomAD3 genomes AF: 0.0276 AC: 4199 AN: 152226 Hom.: 130 Cov.: 32

Gnomad AFR AF: 0.0711

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.0253

GnomAD2 exomes AF: 0.0149 AC: 3474 AN: 232666 AF XY: 0.0144

Gnomad AFR exome AF: 0.0720

Gnomad AMR exome AF: 0.00960

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00376

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.0166

GnomAD4 exome AF: 0.0127 AC: 18379 AN: 1447940 Hom.: 242 Cov.: 32 AF XY: 0.0129 AC XY: 9331 AN XY: 720890

African (AFR) AF: 0.0744 AC: 2489 AN: 33466

American (AMR) AF: 0.00998 AC: 446 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 293 AN: 26106

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.0221 AC: 1903 AN: 86250

European-Finnish (FIN) AF: 0.00331 AC: 132 AN: 39920

Middle Eastern (MID) AF: 0.0339 AC: 195 AN: 5758

European-Non Finnish (NFE) AF: 0.0108 AC: 12007 AN: 1111768

Other (OTH) AF: 0.0151 AC: 912 AN: 60284

GnomAD4 genome AF: 0.0276 AC: 4210 AN: 152344 Hom.: 130 Cov.: 32 AF XY: 0.0275 AC XY: 2049 AN XY: 74502

African (AFR) AF: 0.0711 AC: 2958 AN: 41580

American (AMR) AF: 0.0190 AC: 291 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4832

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10632

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0110 AC: 746 AN: 68034

Other (OTH) AF: 0.0255 AC: 54 AN: 2116

Alfa AF: 0.0198 Hom.: 33

Bravo AF: 0.0309

Asia WGS AF: 0.0160 AC: 54 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0136

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Cyclical neutropenia;C1859966:Neutropenia, severe congenital, 1, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.4
DANN	Benign	0.87
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17223045; hg19: chr19-855587; COSMIC: COSV55049373; COSMIC: COSV55049373;