rs1057520110

Positions:

• chr19-852978-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001972.4(ELANE):​c.170C>T​(p.Ala57Val) 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. A57S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELANE NM_001972.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.674

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 18 ACMG points.

• PM1: In a strand (size 9) in uniprot entity ELNE_HUMAN there are 9 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, 0.993
• PP5: Variant 19-852978-C-T is Pathogenic according to our data. Variant chr19-852978-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 377028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-852978-C-T is described in UniProt as null. Variant chr19-852978-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.170C>T	p.Ala57Val	missense_variant	2/5	ENST00000263621.2	NP_001963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELANE	ENST00000263621.2	c.170C>T	p.Ala57Val	missense_variant	2/5	1	NM_001972.4	ENSP00000263621	P1
ELANE	ENST00000590230.5	c.170C>T	p.Ala57Val	missense_variant	3/6	5		ENSP00000466090	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 02, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Benign	-0.83
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.028	N
LIST_S2	Uncertain	0.96	.;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.9	.;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.97		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.99
MPC		1.2
ClinPred		0.97	D
GERP RS		-6.3
Varity_R		0.63
gMVP		0.97

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: rs1057520110; hg19: chr19-852978;