Variant 3-9890723-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 10P and 8B. PVS1PS1_ModerateBS1BS2

The NM_032492.4(JAGN1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,607,424 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 20 hom. )

Consequence

JAGN1
NM_032492.4 start_lost

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.68

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 Uncertain_significance. Variant got 2 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_032492.4 (JAGN1) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 156113

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00251 (383/152316) while in subpopulation NFE AF= 0.00104 (71/68016). AF 95% confidence interval is 0.000848. There are 8 homozygotes in gnomad4. There are 281 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAGN1	NM_032492.4 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/2	ENST00000647897.1
JAGN1	NM_001363890.1 linkuse as main transcript	c.-268A>G		5_prime_UTR_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAGN1	ENST00000647897.1 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/2		NM_032492.4	P1
JAGN1	ENST00000489724.2 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.00252

AC:

383

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0289

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00338

AC:

793

AN:

234828

Hom.:

AF XY:

0.00323

AC XY:

412

AN XY:

127636

show subpopulations

Gnomad AFR exome

AF:

0.000135

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0322

Gnomad NFE exome

AF:

0.00132

Gnomad OTH exome

AF:

0.00283

GnomAD4 exome

AF:

0.00152

AC:

2213

AN:

1455108

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1073

AN XY:

723294

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.0275

Gnomad4 NFE exome

AF:

0.000596

Gnomad4 OTH exome

AF:

0.00171

GnomAD4 genome

AF:

0.00251

AC:

383

AN:

152316

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

281

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0289

Gnomad4 NFE

AF:

0.00104

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000799

Hom.:

Bravo

AF:

0.000370

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000350

AC:

ExAC

AF:

0.00278

AC:

337

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive severe congenital neutropenia due to JAGN1 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.;T

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

.;D;D

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Uncertain

-0.028

MutationTaster

Benign

1.0

PROVEAN

Uncertain

-3.6

D;.;.

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0

D;.;.

Polyphen

1.0

D;.;D

Vest4

0.96

MVP

0.68

ClinPred

0.14

GERP RS

6.0

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.88

gMVP

0.53

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