NM_001972.4:c.235G>A

Variant names:

• chr19-853272-G-A
• rs769123461
• NM_001972.4:c.235G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_001972.4(ELANE):​c.235G>A​(p.Ala79Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,450,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. A79V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ELANE NM_001972.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.74
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 27 uncertain in NM_001972.4
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23830995).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001972.4. 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.235G>A	p.Ala79Thr	missense	Exon 3 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.235G>A	p.Ala79Thr	missense	Exon 3 of 5	ENSP00000263621.1
	ELANE	ENST00000590230.5	TSL:5	c.235G>A	p.Ala79Thr	missense	Exon 4 of 6	ENSP00000466090.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000898 AC: 2 AN: 222650 AF XY: 0.00000816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1450858 Hom.: 0 Cov.: 35 AF XY: 0.00000416 AC XY: 3 AN XY: 720998

African (AFR) AF: 0.00 AC: 0 AN: 33022

American (AMR) AF: 0.00 AC: 0 AN: 43720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25856

East Asian (EAS) AF: 0.00 AC: 0 AN: 39138

South Asian (SAS) AF: 0.0000236 AC: 2 AN: 84914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107500

Other (OTH) AF: 0.0000167 AC: 1 AN: 59812

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cyclical neutropenia;C1859966:Neutropenia, severe congenital, 1, autosomal dominant (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.12
DANN	Benign	0.78
DEOGEN2	Benign	0.32	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.15	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.46	N
PhyloP100		-1.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.17
Sift	Benign	0.70	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.084
MutPred		0.47		Loss of methylation at R78 (P = 0.0955)
MVP		0.47
MPC		0.47
ClinPred		0.036	T
GERP RS		-1.6
Varity_R		0.088
gMVP		0.64
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs769123461; hg19: chr19-853272;