rs17223045

chr19-855587-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001972.4(ELANE):c.390C>T(p.Asn130=) 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:7
• Conservation: PhyloP100: -1.34

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 258498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-855587-C-T is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELANE	NM_001972.4	c.390C>T	p.Asn130=	synonymous_variant	4/5	ENST00000263621.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELANE	ENST00000263621.2	c.390C>T	p.Asn130=	synonymous_variant	4/5	1	NM_001972.4	P1
ELANE	ENST00000590230.5	c.390C>T	p.Asn130=	synonymous_variant	5/6	5		P1

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

GnomAD3 exomes AF: 0.0149 AC: 3474 AN: 232666 Hom.: 65 AF XY: 0.0144 AC XY: 1846 AN XY: 127970

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 SAS exome AF: 0.0207

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

Gnomad4 AFR exome AF: 0.0744

Gnomad4 AMR exome AF: 0.00998

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0221

Gnomad4 FIN exome AF: 0.00331

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.0151

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

Gnomad4 AFR AF: 0.0711

Gnomad4 AMR AF: 0.0190

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0178

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0197 Hom.: 19

Bravo AF: 0.0309

Asia WGS AF: 0.0160 AC: 54 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0136

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Cyclical neutropenia;C1859966:Neutropenia, severe congenital, 1, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	4.4
Dann	Benign	0.87

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

Publications

LitVar

Other links and lift over

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