rs201117839

Variant names:

• chr19-855957-G-A
• rs201117839
• NM_001972.4:c.598-1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 9P and 4B. PVS1 PP5 BS2

The NM_001972.4(ELANE):​c.598-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000178 in 1,460,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: ELANE NM_001972.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.98
• Publications: 0 publications found

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]

ELANE Gene-Disease associations (from GenCC):

• neutropenia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• cyclic hematopoiesis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant severe congenital neutropenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.4, offset of 1, new splice context is: accttgtctgcctccacaAGggg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 19-855957-G-A is Pathogenic according to our data. Variant chr19-855957-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228343.
• BS2: High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELANE	NM_001972.4	c.598-1G>A		splice_acceptor_variant, intron_variant	Intron 4 of 4	ENST00000263621.2	NP_001963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELANE	ENST00000263621.2	c.598-1G>A		splice_acceptor_variant, intron_variant	Intron 4 of 4	1	NM_001972.4	ENSP00000263621.1
ELANE	ENST00000590230.5	c.598-1G>A		splice_acceptor_variant, intron_variant	Intron 5 of 5	5		ENSP00000466090.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248292 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1460790 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 726706

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1112002

Other (OTH) AF: 0.0000497 AC: 3 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked severe congenital neutropenia Pathogenic:1

Sep 29, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.598-1G>A variant in ELANE has not been previously reported in the literatu reor in large population studies. This variant occurs in the invariant region (+ /- 1,2) of the splice consensus sequence at the 3'splice site of intron 4 and is predicted to cause altered splicing leading to an abnormal or absent protein. Other variants predicted to cause loss of function in the ELANE gene, including several splice variants at this splice junction as well as at 5' splice site of this intron, have been reported in individuals with congenital or cyclic neutrop enia (Horwitz 1999, Kurnikova 2011, Germeshausen 2013). In addition, loss of fun ction variants in the ELANE gene are extremely rare in large population studies (ExAC, http://exac.broadinstitute.org), further supporting a disease causing rol e for loss of function variants in this gene. In summary, this variant meets our criteria to be classified as pathogenic for severe congenital or cyclic neutrop enia in an autosomal dominant manner based upon its predicted impact to the prot ein. -

not provided Uncertain:1

Apr 19, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	26
DANN	Uncertain	0.99
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		6.0
GERP RS		4.5
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.95		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201117839; hg19: chr19-855957;