rs57246956

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001972.4(ELANE):​c.452G>A​(p.Cys151Tyr) variant causes a missense change. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C151S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ELANE
NM_001972.4 missense

Scores

11
6
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 4.43
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a strand (size 8) in uniprot entity ELNE_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001972.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 19-855649-G-A is Pathogenic according to our data. Variant chr19-855649-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 535843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ELANENM_001972.4 linkuse as main transcriptc.452G>A p.Cys151Tyr missense_variant 4/5 ENST00000263621.2 NP_001963.1 P08246

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ELANEENST00000263621.2 linkuse as main transcriptc.452G>A p.Cys151Tyr missense_variant 4/51 NM_001972.4 ENSP00000263621.1 P08246
ELANEENST00000590230.5 linkuse as main transcriptc.452G>A p.Cys151Tyr missense_variant 5/65 ENSP00000466090.1 P08246

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cyclical neutropenia;C1859966:Neutropenia, severe congenital, 1, autosomal dominant Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 04, 2019For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Cys151Ser) has been determined to be pathogenic (PMID: 11675333, 17391497. 21072829, 23463630). This suggests that the cysteine residue is critical for ELANE protein function and that other missense substitutions at this position may also be pathogenic. Additional amino acid changes at this codon, including p.Cys151Phe and p.Cys151Trp have also been reported in affected individuals (PMID: 23463630). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in individuals affected with cyclic neutropenia (PMID: 24523240, 25427142 ). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 151 of the ELANE protein (p.Cys151Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. -
Neutropenia, severe congenital, 1, autosomal dominant Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsAug 28, 2020This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Cyclical neutropenia Other:1
not provided, no classification providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D;D
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.84
.;T
M_CAP
Pathogenic
0.92
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.7
M;M
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-10
.;D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
.;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.92
MutPred
0.97
Loss of catalytic residue at L152 (P = 0.0244);Loss of catalytic residue at L152 (P = 0.0244);
MVP
0.98
MPC
1.8
ClinPred
1.0
D
GERP RS
4.4
Varity_R
0.99
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs57246956; hg19: chr19-855649; API