rs797045009

Variant names:

• chr19-855758-C-A
• rs797045009
• NM_001972.4:c.561C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001972.4(ELANE):​c.561C>A​(p.Cys187*) variant causes a stop gained 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ELANE NM_001972.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.34
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 34 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-855758-C-A is Pathogenic according to our data. Variant chr19-855758-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 208494.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001972.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELANE	NM_001972.4	MANE Select	c.561C>A	p.Cys187*	stop_gained	Exon 4 of 5	NP_001963.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELANE	ENST00000263621.2	TSL:1 MANE Select	c.561C>A	p.Cys187*	stop_gained	Exon 4 of 5	ENSP00000263621.1
	ELANE	ENST00000590230.5	TSL:5	c.561C>A	p.Cys187*	stop_gained	Exon 5 of 6	ENSP00000466090.1
	ELANE	ENST00000958526.1		c.561C>A	p.Cys187*	stop_gained	Exon 5 of 6	ENSP00000628585.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1457090 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724998

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5018

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111916

Other (OTH) AF: 0.00 AC: 0 AN: 60280

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cyclical neutropenia;C1859966:Neutropenia, severe congenital, 1, autosomal dominant (1)
1	-	-	Neutropenia, severe congenital, 1, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		1.3
Vest4		0.75
GERP RS		3.5
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs797045009; hg19: chr19-855758;