chr3-9890781-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_032492.4(JAGN1):c.59G>A(p.Arg20Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,609,484 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

JAGN1
NM_032492.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.41

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]

JAGN1 links:

Genome browser will be placed here

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, 0.978

PP5

Variant 3-9890781-G-A is Pathogenic according to our data. Variant chr3-9890781-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190479.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAGN1	NM_032492.4 link	c.59G>A	p.Arg20Gln	missense_variant	Exon 1 of 2	ENST00000647897.1	NP_115881.3	Q8N5M9
JAGN1	NM_001363890.1 link	c.-210G>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
JAGN1	ENST00000647897.1 link	c.59G>A	p.Arg20Gln	missense_variant	Exon 1 of 2		NM_032492.4	ENSP00000496942.1		Q8N5M9
JAGN1	ENST00000489724.2 link	c.59G>A	p.Arg20Gln	missense_variant	Exon 1 of 2	3		ENSP00000497724.1		A0A3B3ITE9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1457284

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724590

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000227

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

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

Bravo

AF:

0.00000378

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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 -

Autosomal recessive severe congenital neutropenia due to JAGN1 deficiency

Uncertain:1

Sep 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 20 of the JAGN1 protein (p.Arg20Gln). 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. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 190479). This missense change has been observed in individual(s) with severe congenital neutropenia (PMID: 25129144). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

D;.;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.88

.;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Pathogenic

3.1

M;.;M

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.8

D;.;.

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0

D;.;.

Polyphen

1.0

D;.;D

Vest4

0.96

MutPred

0.93

Loss of MoRF binding (P = 0.1007);Loss of MoRF binding (P = 0.1007);Loss of MoRF binding (P = 0.1007);

MVP

0.76

MPC

0.57

ClinPred

0.99

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.89

gMVP

0.76

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over