3-9893366-A-G

Position:

• chr3-9893366-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032492.4(JAGN1):​c.541A>G​(p.Lys181Glu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAGN1 NM_032492.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAGN1	NM_032492.4	c.541A>G	p.Lys181Glu	missense_variant	2/2	ENST00000647897.1	NP_115881.3
JAGN1	NM_001363890.1	c.379A>G	p.Lys127Glu	missense_variant	2/2		NP_001350819.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAGN1	ENST00000647897.1	c.541A>G	p.Lys181Glu	missense_variant	2/2		NM_032492.4	ENSP00000496942.1
JAGN1	ENST00000489724.2	c.*494A>G		3_prime_UTR_variant	2/2	3		ENSP00000497724.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.41	.;T
M_CAP	Benign	0.025	T
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.0	N;.
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.99	D;D
Vest4		0.65
MutPred		0.62		Loss of methylation at K181 (P = 0.0122);Loss of methylation at K181 (P = 0.0122);
MVP		0.67
MPC		0.82
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.80

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

Other links and lift over

dbSNP: rs754191323; hg19: chr3-9935050;