3-9890762-G-A

Variant names:

• chr3-9890762-G-A
• rs786205704
• NM_032492.4:c.40G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_032492.4(JAGN1):​c.40G>A​(p.Gly14Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G14D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAGN1 NM_032492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.41
• Publications: 6 publications found

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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_032492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 3-9890762-G-A is Pathogenic according to our data. Variant chr3-9890762-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190480.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAGN1	NM_032492.4	MANE Select	c.40G>A	p.Gly14Ser	missense	Exon 1 of 2	NP_115881.3
	JAGN1	NM_001363890.1		c.-229G>A		5_prime_UTR	Exon 1 of 2	NP_001350819.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAGN1	ENST00000647897.1	MANE Select	c.40G>A	p.Gly14Ser	missense	Exon 1 of 2	ENSP00000496942.1
	JAGN1	ENST00000489724.2	TSL:3	c.40G>A	p.Gly14Ser	missense	Exon 1 of 2	ENSP00000497724.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000552 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive severe congenital neutropenia due to JAGN1 deficiency Pathogenic:1 Uncertain:1

Apr 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 190480). 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. Experimental studies have shown that this missense change affects JAGN1 function (PMID: 33206996). 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. This missense change has been observed in individual(s) with JAGN1-related conditions (PMID: 25129144, 27980538, 33206996). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 14 of the JAGN1 protein (p.Gly14Ser). This variant is not present in population databases (gnomAD no frequency).

Apr 17, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3_MOD,PM3,PM2_SUP,PP3

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		8.4
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.80		Gain of glycosylation at G14 (P = 0.0341)
MVP		0.81
MPC		0.78
ClinPred		1.0	D
GERP RS		5.8
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.95
gMVP		0.68
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786205704; hg19: chr3-9932446;