rs138211132

Positions:

• chr19-856144-C-A
• chr19-856144-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001972.4(ELANE):​c.784C>A​(p.Pro262Thr) 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 benign outcome for this variant. 14/21 in silico tools predict a benign 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. P262L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELANE NM_001972.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.393

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain Neutrophil elastase (size 237) in uniprot entity ELNE_HUMAN there are 55 pathogenic changes around while only 4 benign (93%) in NM_001972.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13008079).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELANE	NM_001972.4	c.784C>A	p.Pro262Thr	missense_variant	5/5	ENST00000263621.2	NP_001963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELANE	ENST00000263621.2	c.784C>A	p.Pro262Thr	missense_variant	5/5	1	NM_001972.4	ENSP00000263621.1
ELANE	ENST00000590230.5	c.784C>A	p.Pro262Thr	missense_variant	6/6	5		ENSP00000466090.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	3.8
DANN	Benign	0.79
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.38	.;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.90	.;N
REVEL	Benign	0.19
Sift	Benign	0.031	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.42	B;B
Vest4		0.11
MutPred		0.47		Gain of phosphorylation at P262 (P = 0.0062);Gain of phosphorylation at P262 (P = 0.0062);
MVP		0.74
MPC		0.55
ClinPred		0.12	T
GERP RS		1.4
Varity_R		0.049
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs138211132; hg19: chr19-856144;