chr3-9892955-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.79

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive severe congenital neutropenia due to JAGN1 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

JAGN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 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 CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156114. Variant chr3-9892955-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156114. Variant chr3-9892955-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156114.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAGN1	NM_032492.4 link	c.130C>T	p.His44Tyr	missense_variant	Exon 2 of 2	ENST00000647897.1	NP_115881.3	Q8N5M9
JAGN1	NM_001363890.1 link	c.-33C>T		5_prime_UTR_variant	Exon 2 of 2		NP_001350819.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAGN1	ENST00000647897.1 link	c.130C>T	p.His44Tyr	missense_variant	Exon 2 of 2		NM_032492.4	ENSP00000496942.1		Q8N5M9
JAGN1	ENST00000489724.2 link	c.*83C>T		3_prime_UTR_variant	Exon 2 of 2	3		ENSP00000497724.1		A0A3B3ITE9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461714

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111856

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

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

Sep 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 156114). 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. This variant is not present in population databases (gnomAD no frequency). 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). -

not provided

Pathogenic:1

Jun 01, 2019

CeGaT Center for Human Genetics Tuebingen

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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

D;D

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Benign

-0.37

MutationAssessor

Pathogenic

3.1

M;M

PhyloP100

7.8

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.5

D;.

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0030

D;.

Polyphen

0.49

P;P

Vest4

0.68

MutPred

0.77

Gain of catalytic residue at H44 (P = 0.0459);Gain of catalytic residue at H44 (P = 0.0459);

MVP

0.69

MPC

0.28

ClinPred

0.99

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.83

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over