rs587777728
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_032492.4(JAGN1):c.130C>T(p.His44Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,714 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: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
JAGN1
NM_032492.4 missense
NM_032492.4 missense
Scores
9
8
2
Clinical Significance
Conservation
PhyloP100: 7.79
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.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.941
PP5
Variant 3-9892955-C-T is Pathogenic according to our data. Variant chr3-9892955-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 156114.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
JAGN1 | NM_032492.4 | c.130C>T | p.His44Tyr | missense_variant | 2/2 | ENST00000647897.1 | NP_115881.3 | |
JAGN1 | NM_001363890.1 | c.-33C>T | 5_prime_UTR_variant | 2/2 | NP_001350819.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
JAGN1 | ENST00000647897.1 | c.130C>T | p.His44Tyr | missense_variant | 2/2 | NM_032492.4 | ENSP00000496942.1 | |||
JAGN1 | ENST00000489724.2 | c.*83C>T | 3_prime_UTR_variant | 2/2 | 3 | ENSP00000497724.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461714Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727164
GnomAD4 exome
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1
AN:
1461714
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33
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0
AN XY:
727164
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal recessive severe congenital neutropenia due to JAGN1 deficiency Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 16, 2022 | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 44 of the JAGN1 protein (p.His44Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe congenital neutropenia (PMID: 25851723, 32419428). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 156114). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2019 | - - |
Severe congenital neutropenia Pathogenic:1
Pathogenic, criteria provided, single submitter | in vitro | Klein lab, Ludwig-Maximilians-University | Jan 01, 2013 | Neutropenia patients with mutations in JAGN1 respond poorly to treatment with recombinant human G-CSF - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Uncertain
D;.
Polyphen
P;P
Vest4
MutPred
Gain of catalytic residue at H44 (P = 0.0459);Gain of catalytic residue at H44 (P = 0.0459);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at