19-855795-G-C

Position:

• chr19-855795-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001972.4(ELANE):​c.597+1G>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ELANE NM_001972.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.28606966 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
• PP5: Variant 19-855795-G-C is Pathogenic according to our data. Variant chr19-855795-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 245599.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+1G>C		splice_donor_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+1G>C		splice_donor_variant, intron_variant		1	NM_001972.4	ENSP00000263621.1
ELANE	ENST00000590230.5	c.597+1G>C		splice_donor_variant, intron_variant		5		ENSP00000466090.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 16, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.597+1G nucleotide in the ELANE gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10581030, 23463630, 24616599). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 245599). This variant has been observed in individuals with cyclic neutropenia (PMID: 21425445, 34340247; Invitae). 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. It affects a nucleotide within the consensus splice site. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 03, 2015

The c.597+1 G>C splice site mutation in the ELANE gene has been previously reported in association with congenital neutropenia (Kurnikova et al., 2011). This mutation destroys the canonical splice donor site in intron 4, and is expected to cause abnormal gene splicing. Mutations in the IVS4 donor site are the most common category of mutations associated with cyclic neutropenia, but can also be found in association with severe congenital neutropenia. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	25
DANN	Benign	0.90
Eigen	Uncertain	0.52
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.23	N
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		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; COSMIC: COSV105844091; COSMIC: COSV105844091;