rs1555710005

Positions:

• chr19-855795-G-A
• chr19-855795-G-C
• chr19-855795-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1_Strong PM2 PP3_Strong PP5_Very_Strong

The NM_001972.4(ELANE):​c.597+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.000000687 in 1,456,040 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ELANE NM_001972.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.92

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.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.14303483 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.7, offset of -30, new splice context is: ctcGTgagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-855795-G-A is Pathogenic according to our data. Variant chr19-855795-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 242287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELANE	NM_001972.4	c.597+1G>A		splice_donor_variant		ENST00000263621.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELANE	ENST00000263621.2	c.597+1G>A		splice_donor_variant		1	NM_001972.4	P1
ELANE	ENST00000590230.5	c.597+1G>A		splice_donor_variant		5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456040 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724484

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 17, 2020	DNA sequence analysis of the ELANE gene demonstrated a sequence change in the canonical splice donor site of intron 4, c.597+1G>A. This sequence change is absent from large population databases such as ExAC and gnomAD (rs878855318). This sequence change is predicted to affect normal splicing of the ELANE gene and result in an abnormal protein. This variant has been previously described in multiple patients with cyclic neutropenia and severe congenital neutropenia (PMIDs: 10581030, 23463630, and 30171085). It has also been described in a family with severe congenital neutropenia; family members presented with different degrees of the disease severity (PMID: 24616599). RT-PCR analysis of patients' cDNA harboring this variant demonstrated that this sequence change results in the use of a cryptic splice-donor site 30 bases upstream, causing an in-frame deletion of the last 10 amino acid residues from exon 4 (PMID: 10581030). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2021	Observed heterozygous in multiple patients with severe neutropenia or cyclic neutropenia in published literature (Horwitz et al., 1999; Dale et al., 2000; Ancliff et al., 2001; Bellanne-Chantelot et al., 2004; Sera et al., 2005); Observed homozygous in one individual with cyclic neutropenia in published literature (Arun et al., 2018); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16079102, 14962902, 11001877, 30171085, 23463630, 24616599, 10581030, 25525159, 11675333) -

Neutropenia, severe congenital, 1, autosomal dominant Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	UOSD Laboratory of Genetics & Genomics of Rare Diseases, Istituto Giannina Gaslini	May 21, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	Jun 09, 2023	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 28, 2023

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in exon 4 (PMID: 10581030, 23463630). ClinVar contains an entry for this variant (Variation ID: 242287). This variant has been observed in individual(s) with severe congenital neutropenia (PMID: 10581030, 23463630, 24616599). In at least one individual the variant was observed to be de novo. 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 falls in intron 4 of the ELANE gene. It does not directly change the encoded amino acid sequence of the ELANE protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 10 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. -

ELANE-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 09, 2023

The ELANE c.597+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in several families with neutropenia and is known to result in an altered mRNA transcript (Horwitz et al. 1999. PubMed ID: 10581030; Germeshausen et al. 2013. PubMed ID: 23463630; Arun et al. 2018. PubMed ID: 30171085). Similar variants affecting the same splice site, located between exons 4 and 5 of the ELANE gene, have also been reported to cause neutropenia (Kurnikova et al. 2011. PubMed ID: 21425445). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in ELANE are expected to be pathogenic. This variant is interpreted as pathogenic. -

Cyclical neutropenia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Benign	-0.53
CADD	Pathogenic	26
DANN	Benign	0.91
Eigen	Uncertain	0.52
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.51	D
MutationTaster	Benign	1.0	D;D
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555710005; hg19: chr19-855795;