NM_001972.4:c.235G>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 3P and 11B. PM1 PP2 BP4_Moderate BP6 BS1 BS2

The NM_001972.4(ELANE):​c.235G>T​(p.Ala79Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000749 in 1,603,074 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 Conflicting classifications of pathogenicity (no stars). 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: ELANE NM_001972.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B: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: Benign. The variant received -8 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
• 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=0.11020079).
• BP6: Variant 19-853272-G-T is Benign according to our data. Variant chr19-853272-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 618080.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000689 (10/1450856) while in subpopulation AMR AF = 0.000229 (10/43720). AF 95% confidence interval is 0.000123. There are 0 homozygotes in GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 10 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELANE	NM_001972.4	MANE Select	c.235G>T	p.Ala79Ser	missense	Exon 3 of 5	NP_001963.1	P08246

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELANE	ENST00000263621.2	TSL:1 MANE Select	c.235G>T	p.Ala79Ser	missense	Exon 3 of 5	ENSP00000263621.1	P08246
	ELANE	ENST00000590230.5	TSL:5	c.235G>T	p.Ala79Ser	missense	Exon 4 of 6	ENSP00000466090.1	P08246
	ELANE	ENST00000958526.1		c.235G>T	p.Ala79Ser	missense	Exon 4 of 6	ENSP00000628585.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000494 AC: 11 AN: 222650 AF XY: 0.0000326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000333

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000689 AC: 10 AN: 1450856 Hom.: 0 Cov.: 35 AF XY: 0.00000416 AC XY: 3 AN XY: 720996

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

American (AMR) AF: 0.000229 AC: 10 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: 0.00 AC: 0 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: 1107498

Other (OTH) AF: 0.00 AC: 0 AN: 59812

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000503 AC: 6

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	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	0.071
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.029
DANN	Benign	0.52
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00082	N
LIST_S2	Benign	0.14	T
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	-0.26	N
PhyloP100		-1.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.27	N
REVEL	Benign	0.17
Sift	Benign	0.92	T
Sift4G	Benign	0.90	T
Polyphen		0.0	B
Vest4		0.092
MutPred		0.44		Gain of catalytic residue at A79 (P = 0.0464)
MVP		0.47
MPC		0.44
ClinPred		0.061	T
GERP RS		-1.6
Varity_R		0.14
gMVP		0.66
Mutation Taster		=95/5	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;