19-828365-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001700.5(AZU1):​c.194C>T​(p.Ala65Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000271 in 1,589,476 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: 0.000029 ( 0 hom. )

Consequence

AZU1
NM_001700.5 missense

Scores

5
9
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0540
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AZU1NM_001700.5 linkc.194C>T p.Ala65Val missense_variant Exon 2 of 5 ENST00000233997.4 NP_001691.1 P20160

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AZU1ENST00000233997.4 linkc.194C>T p.Ala65Val missense_variant Exon 2 of 5 1 NM_001700.5 ENSP00000233997.1 P20160
AZU1ENST00000592205.5 linkc.8C>T p.Ala3Val missense_variant Exon 2 of 4 2 ENSP00000481172.1 A0A087WXP0

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151222
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000244
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
GnomAD3 exomes
AF:
0.0000215
AC:
5
AN:
232272
Hom.:
0
AF XY:
0.0000157
AC XY:
2
AN XY:
127482
show subpopulations
Gnomad AFR exome
AF:
0.0000673
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000110
Gnomad EAS exome
AF:
0.0000593
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000191
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000285
AC:
41
AN:
1438254
Hom.:
0
Cov.:
32
AF XY:
0.0000238
AC XY:
17
AN XY:
713284
show subpopulations
Gnomad4 AFR exome
AF:
0.0000307
Gnomad4 AMR exome
AF:
0.0000240
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000519
Gnomad4 SAS exome
AF:
0.0000238
Gnomad4 FIN exome
AF:
0.0000387
Gnomad4 NFE exome
AF:
0.0000273
Gnomad4 OTH exome
AF:
0.0000506
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151222
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
73822
show subpopulations
Gnomad4 AFR
AF:
0.0000244
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000607
Hom.:
0
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 05, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.194C>T (p.A65V) 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 194, causing the alanine (A) at amino acid position 65 to be replaced by a valine (V). 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
0.68
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
0.12
CADD
Benign
16
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
.;D
Eigen
Benign
0.098
Eigen_PC
Benign
-0.25
FATHMM_MKL
Benign
0.14
N
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.84
D;D
MetaSVM
Uncertain
0.50
D
MutationAssessor
Pathogenic
3.5
.;H
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-3.6
.;D
REVEL
Uncertain
0.61
Sift
Pathogenic
0.0
.;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
.;D
Vest4
0.31
MutPred
0.93
.;Loss of sheet (P = 0.1158);
MVP
0.91
MPC
0.20
ClinPred
0.37
T
GERP RS
2.4
Varity_R
0.45
gMVP
0.80

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs746878090; hg19: chr19-828365; COSMIC: COSV99297448; API