rs137854446

Positions:

• chr19-855978-G-C
• chr19-855978-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001972.4(ELANE):​c.618G>C​(p.Leu206Phe) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L206S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELANE NM_001972.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.27

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 12 ACMG points.

• PM1: In a disulfide_bond (size 57) in uniprot entity ELNE_HUMAN there are 10 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, 0.994
• PP5: Variant 19-855978-G-C is Pathogenic according to our data. Variant chr19-855978-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 803508.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELANE	NM_001972.4	c.618G>C	p.Leu206Phe	missense_variant	5/5	ENST00000263621.2	NP_001963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELANE	ENST00000263621.2	c.618G>C	p.Leu206Phe	missense_variant	5/5	1	NM_001972.4	ENSP00000263621.1
ELANE	ENST00000590230.5	c.618G>C	p.Leu206Phe	missense_variant	6/6	5		ENSP00000466090.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cyclical neutropenia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	.;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.5	.;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0040	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.69
MutPred		0.97		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.96
MPC		1.5
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.83
gMVP		0.93

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: rs137854446; hg19: chr19-855978;