rs387906553

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP2

The ENST00000263621.2(ELANE):c.214G>A(p.Val72Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000256 in 1,562,686 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V72L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ELANE
ENST00000263621.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: -0.158

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

neutropenia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
cyclic hematopoiesis
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
autosomal dominant severe congenital neutropenia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ELANE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 20 uncertain in ENST00000263621.2

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 53 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.71822 (below the threshold of 3.09). Trascript score misZ: -0.55649 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant severe congenital neutropenia, cyclic hematopoiesis, neutropenia.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000263621.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELANE	NM_001972.4	MANE Select	c.214G>A	p.Val72Met	missense	Exon 2 of 5	NP_001963.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELANE	ENST00000263621.2	TSL:1 MANE Select	c.214G>A	p.Val72Met	missense	Exon 2 of 5	ENSP00000263621.1
	ELANE	ENST00000590230.5	TSL:5	c.214G>A	p.Val72Met	missense	Exon 3 of 6	ENSP00000466090.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000213

AC:

AN:

1410492

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

699200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32464

American (AMR)

AF:

0.00

AC:

AN:

39214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25490

East Asian (EAS)

AF:

0.00

AC:

AN:

37256

South Asian (SAS)

AF:

0.00

AC:

AN:

81690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5410

European-Non Finnish (NFE)

AF:

0.00000274

AC:

AN:

1093516

Other (OTH)

AF:

0.00

AC:

AN:

58774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Neutropenia, severe congenital, 1, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.52

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.69

M_CAP

Uncertain

0.28

MetaRNN

Uncertain

0.45

MetaSVM

Uncertain

-0.079

MutationAssessor

Benign

1.2

PhyloP100

-0.16

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.050

REVEL

Benign

0.26

Sift

Benign

0.35

Sift4G

Benign

0.27

Polyphen

0.94

Vest4

0.22

MutPred

0.55

Gain of MoRF binding (P = 0.0941)

MVP

0.80

MPC

0.76

ClinPred

0.78

GERP RS

-0.20

Varity_R

0.37

gMVP

0.87

Mutation Taster

=27/73

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over