Variant chr19-828287-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001700.5(AZU1):c.116C>T(p.Pro39Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,611,666 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

AZU1
NM_001700.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.521

Variant links:

Genes affected

AZU1 (HGNC:913): (azurocidin 1) Azurophil granules, specialized lysosomes of the neutrophil, contain at least 10 proteins implicated in the killing of microorganisms. This gene encodes a preproprotein that is proteolytically processed to generate a mature azurophil granule antibiotic protein, with monocyte chemotactic and antimicrobial activity. It is also an important multifunctional inflammatory mediator. This encoded protein is a member of the serine protease gene family but it is not a serine proteinase, because the active site serine and histidine residues are replaced. The genes encoding this protein, neutrophil elastase 2, and proteinase 3 are in a cluster located at chromosome 19pter. All 3 genes are expressed coordinately and their protein products are packaged together into azurophil granules during neutrophil differentiation. [provided by RefSeq, Nov 2015]

AZU1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AZU1	NM_001700.5 link	c.116C>T	p.Pro39Leu	missense_variant	2/5	ENST00000233997.4	NP_001691.1	P20160

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AZU1	ENST00000233997.4 link	c.116C>T	p.Pro39Leu	missense_variant	2/5	1	NM_001700.5	ENSP00000233997.1	P20160
AZU1	ENST00000592205 link	c.-71C>T		5_prime_UTR_premature_start_codon_gain_variant	2/4	2		ENSP00000481172.1	A0A087WXP0
AZU1	ENST00000592205 link	c.-71C>T		5_prime_UTR_variant	2/4	2		ENSP00000481172.1	A0A087WXP0

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000202

AC:

AN:

247788

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134718

show subpopulations

Gnomad AFR exome

AF:

0.0000630

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000656

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1459438

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

725984

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2023

The c.116C>T (p.P39L) alteration is located in exon 2 (coding exon 2) of the AZU1 gene. This alteration results from a C to T substitution at nucleotide position 116, causing the proline (P) at amino acid position 39 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Uncertain

0.33

Eigen_PC

Benign

0.030

FATHMM_MKL

Benign

0.17

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.9

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-8.6

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.53

MutPred

0.91

Loss of disorder (P = 0.0614);

MVP

0.96

MPC

0.74

ClinPred

1.0

GERP RS

2.3

Varity_R

0.68

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over