19-852990-C-T

Position:

chr19-852990-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001972.4(ELANE):c.182C>T(p.Ala61Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

ELANE
NM_001972.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: -0.727

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 Pathogenic. Variant got 16 ACMG points.

PM1

In a disulfide_bond (size 16) in uniprot entity ELNE_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_001972.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 19-852990-C-T is Pathogenic according to our data. Variant chr19-852990-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-852990-C-T is described in UniProt as null. Variant chr19-852990-C-T is described in UniProt as null. Variant chr19-852990-C-T is described in UniProt as null. Variant chr19-852990-C-T is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELANE	NM_001972.4 linkuse as main transcript	c.182C>T	p.Ala61Val	missense_variant	2/5	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.182C>T	p.Ala61Val	missense_variant	2/5	1	NM_001972.4	ENSP00000263621	P1
ELANE	ENST00000590230.5 linkuse as main transcript	c.182C>T	p.Ala61Val	missense_variant	3/6	5		ENSP00000466090	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1427446

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709058

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.08e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.00467

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

May 20, 2023

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ELANE protein function. ClinVar contains an entry for this variant (Variation ID: 16740). This variant is also known as p.Ala32Val. This missense change has been observed in individual(s) with congenital neutropenia and/or cyclic neutropenia (PMID: 10581030, 11675333, 19036076, 23463630, 25703294). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 61 of the ELANE protein (p.Ala61Val). -

Cyclical neutropenia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1999

- -

Autoinflammatory syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2018

- -

Neutropenia, severe congenital, 1, autosomal dominant

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Oct 23, 2023

This heterozygous mis-sense variant is identified in a 2.6 years girl with recurrent mucosal infection, oral candidiasis, cervical adenopathy, and severe neutropenia with ANC 230, suggestive of congenital neutropenia. This nucleotide change is absent in gnomAD database [PM2]. Insilico prediction [REVEL: 0.5] predicts uncertain nature of this variant. A clinvar entry for this variant is available. This variant is submitted to clinvar database [Variation ID: 16740] with “Pathogenic” interpretation by multiple submitter [PP5]. 9 pathogenic or likely pathogenic reported variants are found surrounding this region in exon 2 without any mis-sense benign change, considering this as a hotspot region [PM1]. PMID [23463630] Based on the clinical correlation and available evidence, this variant is classified as "Likely Pathogenic" -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;D

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.77

.;T

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

1.0

D;D

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

1.6

L;L

MutationTaster

Benign

0.0000035

A;A

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.4

.;N

REVEL

Uncertain

0.57

Sift

Benign

0.11

.;T

Sift4G

Benign

0.085

T;T

Polyphen

1.0

D;D

Vest4

0.82

MutPred

0.89

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.98

MPC

1.1

ClinPred

0.71

GERP RS

3.2

Varity_R

0.64

gMVP

0.93

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