rs137854448

chr19-855613-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_001972.4(ELANE):c.416C>T(p.Pro139Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P139R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ELANE NM_001972.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 0.778

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_001972.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-855613-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2138170.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 19-855613-C-T is Pathogenic according to our data. Variant chr19-855613-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-855613-C-T is described in UniProt as null. Variant chr19-855613-C-T is described in UniProt as null. Variant chr19-855613-C-T is described in UniProt as null. Variant chr19-855613-C-T is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELANE	NM_001972.4	c.416C>T	p.Pro139Leu	missense_variant	4/5	ENST00000263621.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELANE	ENST00000263621.2	c.416C>T	p.Pro139Leu	missense_variant	4/5	1	NM_001972.4	P1
ELANE	ENST00000590230.5	c.416C>T	p.Pro139Leu	missense_variant	5/6	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450270 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 721936

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 28, 2022	PP1, PP3, PM2, PS3_moderate, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 28, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2023	The ELANE c.416C>T; p.Pro139Leu variant (rs137854448), also known as Pro110Leu for legacy numbering, is reported in individuals with neutropenia (Dale 2000, Engelbrecht 2021, Kurnikova 2011, Olcay 2018, Platt 2021). This variant is also reported in ClinVar (Variation ID: 16743). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.793). Based on available information, this variant is considered to be pathogenic. References: Dale DC et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood. 2000 Oct 1;96(7):2317-22. PMID: 11001877. Engelbrecht C et al. Clinical Utility of Whole Exome Sequencing and Targeted Panels for the Identification of Inborn Errors of Immunity in a Resource-Constrained Setting. Front Immunol. 2021 May 21;12:665621. PMID: 34093558. Kurnikova M et al. Four novel ELANE mutations in patients with congenital neutropenia. Pediatr Blood Cancer. 2011 Aug;57(2):332-5. PMID: 21425445. Olcay L et al. Both Granulocytic and Non-Granulocytic Blood Cells Are Affected in Patients with Severe Congenital Neutropenia and Their Non-Neutropenic Family Members: An Evaluation of Morphology, Function, and Cell Death. Turk J Haematol. 2018 Nov 13;35(4):229-259. PMID: 30040071. Platt CD et al. Efficacy and economics of targeted panel versus whole-exome sequencing in 878 patients with suspected primary immunodeficiency. J Allergy Clin Immunol. 2021 Feb;147(2):723-726. PMID: 32888943. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2018	The P139L missense variant has been reported previously in association with neutropenia (Dale et al., 2000; Bellanné-Chantelot et al., 2004; Kurnikova et al.; 2011). The variant is not observed in large population cohorts (Lek et al., 2016). P139L is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the neutrophil elastase peptidase S1 domain that is conserved across species and lacks benign variation. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same (P139R) and in nearby residues (A136D, R143H) have been reported in the Human Gene Mutation Database in association with congenital neutropenia (Stenson et al., 2014), supporting the functional importance of this region of the protein. The presence of the P139L pathogenic variant is consistent with a diagnosis of an ELANE-related neutropenia. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 18, 2018	- -

Cyclical neutropenia;C1859966:Neutropenia, severe congenital, 1, autosomal dominant Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 22, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 139 of the ELANE protein (p.Pro139Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cyclical neutropenia and neutropenia (PMID: 11001877, 14962902, 21425445, 23463630, 30040071; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as P110L. ClinVar contains an entry for this variant (Variation ID: 16743). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ELANE protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Neutropenia, severe congenital, 1, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2008

- -

Cyclical neutropenia Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.75	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.46	T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.56
MutPred		0.92		Gain of MoRF binding (P = 0.0522);Gain of MoRF binding (P = 0.0522);
MVP		0.99
MPC		1.4
ClinPred		0.93	D
GERP RS		4.4
Varity_R		0.92
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs137854448; hg19: chr19-855613;