rs879253882

Positions:

• chr19-855799-G-A
• chr19-855799-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001972.4(ELANE):​c.597+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ELANE NM_001972.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.67

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.

• 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 19-855799-G-A is Pathogenic according to our data. Variant chr19-855799-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 245598.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
ELANE	NM_001972.4	c.597+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000263621.2	NP_001963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELANE	ENST00000263621.2	c.597+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_001972.4	ENSP00000263621	P1
ELANE	ENST00000590230.5	c.597+5G>A		splice_donor_5th_base_variant, intron_variant		5		ENSP00000466090	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455756 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724382

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. It is hypothesied that the enzyme is no longer inhibited or properly packaged, leading to accelerated apoptosis of neutrophils (GeneReviews). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The same variant can lead to either cyclic or severe congenital neutropenia (GeneReviews). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. mRNA expression studies from affected individuals demonstrated the use of a cryptic splice site, leading to an in-frame deletion p.(Val190_Phe199del) (PMIDs: 11001877, 23463630). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten families with either cyclic or severe congenital neutropenia (PMIDs: 10581030, 11001877, 20049848, 23463630, 34340247). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 06, 2023

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 a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with cyclic neutropenia or severe congenital neutropenia (PMID: 10581030, 20049848, 23463630, 30040071). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS4+5G>A. ClinVar contains an entry for this variant (Variation ID: 245598). 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 skipping of the last 10 residues of exon 4 (Val190-Phe199), but is expected to preserve the integrity of the reading-frame (PMID: 23463630). For these reasons, this variant has been classified as Pathogenic. -

Cyclical neutropenia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1999

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2021

Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, 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: 10581030, 21161286, 20049848, 25502423, 23463630, 30040071, 32581362, 31321910, 21659346, 25525159) -

Neutropenia Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	20
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.74		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs879253882; hg19: chr19-855799;