19-828287-C-T

Variant names:

• chr19-828287-C-T
• rs773012210
• NM_001700.5:c.116C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.521

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]

ACMG classification

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 rank	MANE	Protein	UniProt
AZU1	NM_001700.5	c.116C>T	p.Pro39Leu	missense_variant	Exon 2 of 5	ENST00000233997.4	NP_001691.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AZU1	ENST00000233997.4	c.116C>T	p.Pro39Leu	missense_variant	Exon 2 of 5	1	NM_001700.5	ENSP00000233997.1
AZU1	ENST00000592205	c.-71C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 4	2		ENSP00000481172.1
AZU1	ENST00000592205	c.-71C>T		5_prime_UTR_variant	Exon 2 of 4	2		ENSP00000481172.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152228 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

GnomAD3 exomes AF: 0.0000202 AC: 5 AN: 247788 Hom.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134718

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: 12 AN: 1459438 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 725984

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: 2 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

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: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.030
FATHMM_MKL	Benign	0.17	N
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.91		Loss of disorder (P = 0.0614);
MVP		0.96
MPC		0.74
ClinPred		1.0	D
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

Other links and lift over

dbSNP: rs773012210; hg19: chr19-828287;