rs17216663

Positions:

chr19-856130-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_001972.4(ELANE):c.770C>T(p.Pro257Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00743 in 1,613,032 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0059 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0076 ( 57 hom. )

Consequence

ELANE
NM_001972.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.526

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 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

BP4

Computational evidence support a benign effect (MetaRNN=0.0060737133).

BP6

Variant 19-856130-C-T is Benign according to our data. Variant chr19-856130-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-856130-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00587 (894/152358) while in subpopulation NFE AF= 0.00907 (617/68024). AF 95% confidence interval is 0.00848. There are 6 homozygotes in gnomad4. There are 413 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 894 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELANE	NM_001972.4 linkuse as main transcript	c.770C>T	p.Pro257Leu	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 linkuse as main transcript	c.770C>T	p.Pro257Leu	missense_variant	5/5	1	NM_001972.4	ENSP00000263621	P1
ELANE	ENST00000590230.5 linkuse as main transcript	c.770C>T	p.Pro257Leu	missense_variant	6/6	5		ENSP00000466090	P1

Frequencies

GnomAD3 genomes

AF:

0.00587

AC:

893

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00877

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00641

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00907

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.00640

AC:

1596

AN:

249410

Hom.:

AF XY:

0.00670

AC XY:

908

AN XY:

135434

show subpopulations

Gnomad AFR exome

AF:

0.000626

Gnomad AMR exome

AF:

0.00764

Gnomad ASJ exome

AF:

0.0131

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00516

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.00855

Gnomad OTH exome

AF:

0.00886

GnomAD4 exome

AF:

0.00759

AC:

11091

AN:

1460674

Hom.:

Cov.:

AF XY:

0.00766

AC XY:

5563

AN XY:

726600

show subpopulations

Gnomad4 AFR exome

AF:

0.00170

Gnomad4 AMR exome

AF:

0.00825

Gnomad4 ASJ exome

AF:

0.0127

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00556

Gnomad4 FIN exome

AF:

0.00119

Gnomad4 NFE exome

AF:

0.00835

Gnomad4 OTH exome

AF:

0.00734

GnomAD4 genome

AF:

0.00587

AC:

894

AN:

152358

Hom.:

Cov.:

AF XY:

0.00554

AC XY:

413

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00127

Gnomad4 AMR

AF:

0.00882

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00642

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00907

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.00811

Hom.:

Bravo

AF:

0.00631

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0108

AC:

ExAC

AF:

0.00591

AC:

717

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0115

EpiControl

AF:

0.0132

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 06, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 23454784, 11675333, 22995991, 27153395, 18043239) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ELANE: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 01, 2016	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.33

T;T

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.38

.;T

MetaRNN

Benign

0.0061

T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

0.98

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.97

.;N

REVEL

Benign

0.12

Sift

Uncertain

0.0080

.;D

Sift4G

Benign

0.20

T;T

Polyphen

0.010

B;B

Vest4

0.19

MVP

0.63

MPC

0.56

ClinPred

0.022

GERP RS

1.2

Varity_R

0.058

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over