rs17216656

chr19-856015-G-Achr19-856015-G-Cchr19-856015-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001972.4(ELANE):c.655G>A(p.Val219Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,613,536 control chromosomes in the GnomAD database, including 44 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 0.0088 (22 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (22 hom.)
• Consequence: ELANE NM_001972.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.301

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001972.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.008954734).
• BP6: Variant 19-856015-G-A is Benign according to our data. Variant chr19-856015-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-856015-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00885 (1348/152340) while in subpopulation AFR AF= 0.0307 (1277/41570). AF 95% confidence interval is 0.0293. There are 22 homozygotes in gnomad4. There are 635 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1344 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELANE	NM_001972.4	c.655G>A	p.Val219Ile	missense_variant	5/5	ENST00000263621.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELANE	ENST00000263621.2	c.655G>A	p.Val219Ile	missense_variant	5/5	1	NM_001972.4	P1
ELANE	ENST00000590230.5	c.655G>A	p.Val219Ile	missense_variant	6/6	5		P1

Frequencies

GnomAD3 genomes AF: 0.00883 AC: 1344 AN: 152222 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0307

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00225 AC: 564 AN: 250830 Hom.: 7 AF XY: 0.00167 AC XY: 227 AN XY: 135824

Gnomad AFR exome AF: 0.0283

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00359

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000945 AC: 1381 AN: 1461196 Hom.: 22 Cov.: 33 AF XY: 0.000777 AC XY: 565 AN XY: 726900

Gnomad4 AFR exome AF: 0.0307

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00421

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00885 AC: 1348 AN: 152340 Hom.: 22 Cov.: 32 AF XY: 0.00852 AC XY: 635 AN XY: 74498

Gnomad4 AFR AF: 0.0307

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00367

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00226 Hom.: 6

Bravo AF: 0.00996

ESP6500AA AF: 0.0243 AC: 107

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00278 AC: 338

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 07, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2018	This variant is associated with the following publications: (PMID: 20981092, 27884173, 14962902) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Cyclical neutropenia Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	2.4
Dann	Benign	0.80
DEOGEN2	Uncertain	0.42	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.056	N
MetaRNN	Benign	0.0090	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.23	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
Sift4G	Benign	0.98	T;T
Polyphen		0.0030	B;B
Vest4		0.14
MVP		0.43
MPC		0.39
ClinPred		0.00048	T
GERP RS		-1.6
Varity_R		0.11
gMVP		0.61

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: rs17216656; hg19: chr19-856015; COSMIC: COSV55047502; COSMIC: COSV55047502;