3-9890725-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_ModeratePS1_ModeratePM2PP5

The NM_032492.4(JAGN1):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,607,564 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: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

JAGN1
NM_032492.4 start_lost

Scores

9
6
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 8.25
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 72 CDS bases. Genomic position: 9890794. Lost 0.130 part of the original CDS.
PS1
Another start lost variant in NM_032492.4 (JAGN1) was described as [Likely_pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-9890725-G-A is Pathogenic according to our data. Variant chr3-9890725-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 156113.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
JAGN1NM_032492.4 linkc.3G>A p.Met1? start_lost Exon 1 of 2 ENST00000647897.1 NP_115881.3 Q8N5M9
JAGN1NM_001363890.1 linkc.-266G>A 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.3G>A p.Met1? start_lost Exon 1 of 2 NM_032492.4 ENSP00000496942.1 Q8N5M9
JAGN1ENST00000489724.2 linkc.3G>A p.Met1? start_lost Exon 1 of 2 3 ENSP00000497724.1 A0A3B3ITE9

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152220
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.000288
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:
0.000478
GnomAD3 exomes
AF:
0.0000383
AC:
9
AN:
234802
Hom.:
0
AF XY:
0.0000157
AC XY:
2
AN XY:
127606
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000182
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:
0.0000189
Gnomad OTH exome
AF:
0.000177
GnomAD4 exome
AF:
0.0000172
AC:
25
AN:
1455344
Hom.:
0
Cov.:
31
AF XY:
0.0000111
AC XY:
8
AN XY:
723436
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000229
Gnomad4 ASJ exome
AF:
0.000116
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152220
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000604
ExAC
AF:
0.0000413
AC:
5

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal recessive severe congenital neutropenia due to JAGN1 deficiency Pathogenic:2Uncertain:1
Sep 01, 2014
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jul 05, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects the initiator methionine of the JAGN1 mRNA. The next in-frame methionine is located at codon 25. This variant is present in population databases (rs587777727, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with primary immunodeficiency and/or severe congenital neutropenia (PMID: 25129144, 32888943, 33718801). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 156113). This variant disrupts the p.Met1 amino acid residue in JAGN1. Other variant(s) that disrupt this residue have been determined to be benign based on frequency in the population databases (c.1A>G, ExAC). Therefore the functional significance of this variant is uncertain. 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. -

Dec 28, 2021
Genomics Facility, Ludwig-Maximilians-Universität München
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Severe congenital neutropenia Pathogenic:1
Jan 01, 2013
Klein lab, Ludwig-Maximilians-University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: in vitro

Neutropenia patients with mutations in JAGN1 respond poorly to treatment with recombinant human G-CSF -

not provided Uncertain:1
May 18, 2021
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Initiation codon variant in a gene for which loss-of-function is not a known mechanism of disease; Another variant affecting the initiation codon, c.1A>G, is observed in 0.35% (940/266206 alleles) in large population cohorts, including 14 homozygous observations (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32419428, 25129144, 32888943, 33718801) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.45
T;.;T
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.90
.;D;D
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.93
D;D;D
MetaSVM
Uncertain
0.062
D
PROVEAN
Uncertain
-3.6
D;.;.
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
D;.;.
Sift4G
Pathogenic
0.0
D;.;.
Polyphen
1.0
D;.;D
Vest4
0.97
MutPred
0.74
Loss of MoRF binding (P = 0.0717);Loss of MoRF binding (P = 0.0717);Loss of MoRF binding (P = 0.0717);
MVP
0.74
ClinPred
0.96
D
GERP RS
6.0
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.7
Varity_R
0.90
gMVP
0.48

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs587777727; hg19: chr3-9932409; API