NM_032492.4:c.56A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP6

The NM_032492.4(JAGN1):ā€‹c.56A>Gā€‹(p.His19Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,609,802 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.000012 ( 0 hom. )

Consequence

JAGN1
NM_032492.4 missense

Scores

10
7
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 6.05
Variant links:
Genes affected
JAGN1 (HGNC:26926): (jagunal homolog 1) The protein encoded by this gene is a transmembrane protein. It functions in the early secretory pathway and is necessary for neutrophil differentiation and survival. Mutations in this gene result in severe congenital neutropenia. [provided by RefSeq, Oct 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.746
BP6
Variant 3-9890778-A-G is Benign according to our data. Variant chr3-9890778-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 943976.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
JAGN1NM_032492.4 linkc.56A>G p.His19Arg missense_variant Exon 1 of 2 ENST00000647897.1 NP_115881.3 Q8N5M9
JAGN1NM_001363890.1 linkc.-213A>G 5_prime_UTR_variant Exon 1 of 2 NP_001350819.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
JAGN1ENST00000647897.1 linkc.56A>G p.His19Arg missense_variant Exon 1 of 2 NM_032492.4 ENSP00000496942.1 Q8N5M9
JAGN1ENST00000489724.2 linkc.56A>G p.His19Arg missense_variant Exon 1 of 2 3 ENSP00000497724.1 A0A3B3ITE9

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000588
AC:
14
AN:
238224
Hom.:
0
AF XY:
0.0000463
AC XY:
6
AN XY:
129468
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000420
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS 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:
0.0000123
AC:
18
AN:
1457628
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
724802
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000386
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152174
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
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:
0.0000113
ExAC
AF:
0.0000412
AC:
5

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal recessive severe congenital neutropenia due to JAGN1 deficiency Uncertain:1Benign:1
Sep 20, 2024
3billion, Medical Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant. -

Dec 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 19 of the JAGN1 protein (p.His19Arg). This variant is present in population databases (rs748123071, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with JAGN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 943976). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.85
D;.;D
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.87
.;D;D
M_CAP
Benign
0.034
D
MetaRNN
Pathogenic
0.75
D;D;D
MetaSVM
Uncertain
0.073
D
MutationAssessor
Pathogenic
3.0
M;.;M
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-6.3
D;.;.
REVEL
Uncertain
0.58
Sift
Uncertain
0.0050
D;.;.
Sift4G
Uncertain
0.010
D;.;.
Polyphen
0.99
D;.;D
Vest4
0.91
MutPred
0.66
Gain of MoRF binding (P = 0.0131);Gain of MoRF binding (P = 0.0131);Gain of MoRF binding (P = 0.0131);
MVP
0.83
MPC
0.58
ClinPred
0.92
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.86
gMVP
0.70

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: rs748123071; hg19: chr3-9932462; API