19-855574-C-T

Position:

• chr19-855574-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001972.4(ELANE):​c.377C>T​(p.Ser126Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar 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 criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: -0.811

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 domain Peptidase S1 (size 217) in uniprot entity ELNE_HUMAN there are 55 pathogenic changes around while only 2 benign (96%) in NM_001972.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 19-855574-C-T is Pathogenic according to our data. Variant chr19-855574-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-855574-C-T is described in UniProt as null. Variant chr19-855574-C-T is described in UniProt as null. Variant chr19-855574-C-T is described in UniProt as null. Variant chr19-855574-C-T is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELANE	NM_001972.4	c.377C>T	p.Ser126Leu	missense_variant	4/5	ENST00000263621.2	NP_001963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELANE	ENST00000263621.2	c.377C>T	p.Ser126Leu	missense_variant	4/5	1	NM_001972.4	ENSP00000263621.1
ELANE	ENST00000590230.5	c.377C>T	p.Ser126Leu	missense_variant	5/6	5		ENSP00000466090.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1447158 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 720480

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

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neutropenia, severe congenital, 1, autosomal dominant Pathogenic:3

Pathogenic, no assertion criteria provided	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Jun 12, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 25, 2024	- -

Cyclical neutropenia Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 21, 2016

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 14, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ELANE function (PMID: 16551967, 26567890). 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. ClinVar contains an entry for this variant (Variation ID: 16745). This variant is also known as p.Ser97Leu. This missense change has been observed in individuals with cyclic neutropenia and severe congenital neutropenia (PMID: 11001877, 14962902, 16079102, 16737875, 18611981, 20582973, 22758217, 23463630). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 126 of the ELANE protein (p.Ser126Leu). -

ELANE-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2024

The ELANE c.377C>T variant is predicted to result in the amino acid substitution p.Ser126Leu. This variant is also described using legacy nomenclature as p.Ser97Leu, has been reported in multiple individuals with congenital neutropenia (Dale et al. 2000. PubMed ID: 11001877; Sera et al. 2005. PubMed ID: 16079102; Newburger et al. 2010. PubMed ID: 20582973; Wali et al. 2012. PubMed ID: 22758217; Gong et al. 2018. PubMed ID: 30386760). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;D
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.69	.;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.3	.;N
REVEL	Uncertain	0.59
Sift	Benign	0.25	.;T
Sift4G	Benign	0.29	T;T
Polyphen		0.43	B;B
Vest4		0.25
MutPred		0.89		Loss of glycosylation at S126 (P = 0.0876);Loss of glycosylation at S126 (P = 0.0876);
MVP		0.98
MPC		0.47
ClinPred		0.32	T
GERP RS		2.1
Varity_R		0.24
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs137854450; hg19: chr19-855574;