rs35365817

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032492.4(JAGN1):c.244A>G(p.Ile82Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 1,614,078 control chromosomes in the GnomAD database, including 934 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 56 hom., cov: 32)

Exomes 𝑓: 0.032 ( 878 hom. )

Consequence

JAGN1
NM_032492.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.58

Publications

10 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057839453).

BP6

Variant 3-9893069-A-G is Benign according to our data. Variant chr3-9893069-A-G is described in ClinVar as Benign. ClinVar VariationId is 475246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0227 (3461/152258) while in subpopulation NFE AF = 0.0365 (2485/68016). AF 95% confidence interval is 0.0353. There are 56 homozygotes in GnomAd4. There are 1584 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAGN1	NM_032492.4 link	c.244A>G	p.Ile82Val	missense_variant	Exon 2 of 2	ENST00000647897.1	NP_115881.3
JAGN1	NM_001363890.1 link	c.82A>G	p.Ile28Val	missense_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.244A>G	p.Ile82Val	missense_variant	Exon 2 of 2		NM_032492.4	ENSP00000496942.1
JAGN1	ENST00000489724.2 link	c.*197A>G		3_prime_UTR_variant	Exon 2 of 2	3		ENSP00000497724.1

Frequencies

GnomAD3 genomes

AF:

0.0227

AC:

3461

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00707

Gnomad AMI

AF:

0.0363

Gnomad AMR

AF:

0.0234

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00892

Gnomad FIN

AF:

0.0104

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0365

Gnomad OTH

AF:

0.0230

GnomAD2 exomes

AF:

0.0224

AC:

5638

AN:

251454

AF XY:

0.0229

show subpopulations

Gnomad AFR exome

AF:

0.00634

Gnomad AMR exome

AF:

0.0157

Gnomad ASJ exome

AF:

0.0179

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0110

Gnomad NFE exome

AF:

0.0368

Gnomad OTH exome

AF:

0.0272

GnomAD4 exome

AF:

0.0319

AC:

46639

AN:

1461820

Hom.:

878

Cov.:

AF XY:

0.0313

AC XY:

22788

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00481

AC:

161

AN:

33480

American (AMR)

AF:

0.0172

AC:

768

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

468

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00792

AC:

683

AN:

86258

European-Finnish (FIN)

AF:

0.0119

AC:

634

AN:

53420

Middle Eastern (MID)

AF:

0.0184

AC:

106

AN:

5768

European-Non Finnish (NFE)

AF:

0.0379

AC:

42159

AN:

1111944

Other (OTH)

AF:

0.0275

AC:

1660

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

2571

5142

7712

10283

12854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1518

3036

4554

6072

7590

<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

AF:

0.0227

AC:

3461

AN:

152258

Hom.:

Cov.:

AF XY:

0.0213

AC XY:

1584

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00705

AC:

293

AN:

41554

American (AMR)

AF:

0.0234

AC:

358

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00892

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0104

AC:

110

AN:

10608

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0365

AC:

2485

AN:

68016

Other (OTH)

AF:

0.0228

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

176

352

527

703

879

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0319

Hom.:

322

Bravo

AF:

0.0235

TwinsUK

AF:

0.0343

AC:

127

ALSPAC

AF:

0.0431

AC:

166

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.0349

AC:

300

ExAC

AF:

0.0231

AC:

2810

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0402

EpiControl

AF:

0.0385

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive severe congenital neutropenia due to JAGN1 deficiency

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.31

T;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.66

.;T

MetaRNN

Benign

0.0058

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

2.6

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.54

N;.

REVEL

Benign

0.10

Sift

Benign

0.13

T;.

Sift4G

Benign

0.81

T;.

Polyphen

0.078

B;B

Vest4

0.10

MPC

0.18

ClinPred

0.0083

GERP RS

-0.0094

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.035

gMVP

0.42

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over