ENST00000590230.5:c.-120-105C>A

Variant names:

• chr19-852104-C-A
• rs740021
• ENST00000590230.5:c.-120-105C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000590230.5(ELANE):​c.-120-105C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0628 in 596,156 control chromosomes in the GnomAD database, including 3,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (1352 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2574 hom.)
• Consequence: ELANE ENST00000590230.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.130
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-852104-C-A is Benign according to our data. Variant chr19-852104-C-A is described in ClinVar as Benign. ClinVar VariationId is 677093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000590230.5. 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.-225C>A		upstream_gene	N/A	NP_001963.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELANE	ENST00000590230.5	TSL:5	c.-120-105C>A		intron	N/A	ENSP00000466090.1
	ELANE	ENST00000263621.2	TSL:1 MANE Select	c.-225C>A		upstream_gene	N/A	ENSP00000263621.1

Frequencies

GnomAD3 genomes AF: 0.0886 AC: 13484 AN: 152132 Hom.: 1352 Cov.: 32

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0795

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0379

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00777

Gnomad OTH AF: 0.0761

GnomAD4 exome AF: 0.0539 AC: 23918 AN: 443906 Hom.: 2574 AF XY: 0.0551 AC XY: 12849 AN XY: 233006

African (AFR) AF: 0.217 AC: 2646 AN: 12208

American (AMR) AF: 0.0899 AC: 1652 AN: 18382

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 191 AN: 13654

East Asian (EAS) AF: 0.336 AC: 10341 AN: 30740

South Asian (SAS) AF: 0.103 AC: 4603 AN: 44820

European-Finnish (FIN) AF: 0.0342 AC: 1007 AN: 29452

Middle Eastern (MID) AF: 0.0354 AC: 69 AN: 1948

European-Non Finnish (NFE) AF: 0.00744 AC: 1986 AN: 266882

Other (OTH) AF: 0.0551 AC: 1423 AN: 25820

GnomAD4 genome AF: 0.0888 AC: 13517 AN: 152250 Hom.: 1352 Cov.: 32 AF XY: 0.0923 AC XY: 6868 AN XY: 74448

African (AFR) AF: 0.213 AC: 8829 AN: 41522

American (AMR) AF: 0.0798 AC: 1221 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3472

East Asian (EAS) AF: 0.329 AC: 1697 AN: 5162

South Asian (SAS) AF: 0.125 AC: 602 AN: 4824

European-Finnish (FIN) AF: 0.0379 AC: 403 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00778 AC: 529 AN: 68032

Other (OTH) AF: 0.0791 AC: 167 AN: 2112

Alfa AF: 0.0552 Hom.: 1221

Bravo AF: 0.0982

Asia WGS AF: 0.211 AC: 733 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.53
PhyloP100		-0.13
PromoterAI		0.00080	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs740021; hg19: chr19-852104;