rs201664319

Positions:

• chr19-855987-C-A
• chr19-855987-C-G
• chr19-855987-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_001972.4(ELANE):​c.627C>A​(p.Asn209Lys) variant causes a missense 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N209I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELANE NM_001972.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.37

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001972.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELANE	NM_001972.4	c.627C>A	p.Asn209Lys	missense_variant	5/5	ENST00000263621.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELANE	ENST00000263621.2	c.627C>A	p.Asn209Lys	missense_variant	5/5	1	NM_001972.4	P1
ELANE	ENST00000590230.5	c.627C>A	p.Asn209Lys	missense_variant	6/6	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.0094	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	6.2
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;D
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.14	N
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	-0.028	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.55	D;D
PrimateAI	Uncertain	0.51	T
Sift4G	Uncertain	0.030	D;D
Polyphen		0.99	D;D
Vest4		0.27
MutPred		0.59		Gain of methylation at N209 (P = 0);Gain of methylation at N209 (P = 0);
MVP		0.93
MPC		1.3
ClinPred		0.66	D
GERP RS		1.6
Varity_R		0.23
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs201664319; hg19: chr19-855987;