19-852990-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A61E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ELANE NM_001972.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.727

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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	UniProt
ELANE	NM_001972.4	c.182C>T	p.Ala61Val	missense_variant	2/5	ENST00000263621.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELANE	ENST00000263621.2	c.182C>T	p.Ala61Val	missense_variant	2/5	1	NM_001972.4	P1
ELANE	ENST00000590230.5	c.182C>T	p.Ala61Val	missense_variant	3/6	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427446 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 709058

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.: 32

Alfa AF: 0.00467 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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	D
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;D
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.12	N
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.0000035	A;A
PrimateAI	Uncertain	0.65	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	D
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

Other links and lift over

dbSNP: rs137854447; hg19: chr19-852990; COSMIC: COSV99311562; COSMIC: COSV99311562;