rs61746084

chr3-9893228-G-Achr3-9893228-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_032492.4(JAGN1):c.403G>A(p.Ala135Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00196 in 1,614,182 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: JAGN1 NM_032492.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.91

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009364098).
• BP6: Variant 3-9893228-G-A is Benign according to our data. Variant chr3-9893228-G-A is described in ClinVar as [Benign]. Clinvar id is 475248.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-9893228-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0102 (1553/152292) while in subpopulation AFR AF= 0.0351 (1458/41562). AF 95% confidence interval is 0.0336. There are 30 homozygotes in gnomad4. There are 753 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAGN1	NM_032492.4	c.403G>A	p.Ala135Thr	missense_variant	2/2	ENST00000647897.1
JAGN1	NM_001363890.1	c.241G>A	p.Ala81Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAGN1	ENST00000647897.1	c.403G>A	p.Ala135Thr	missense_variant	2/2		NM_032492.4	P1
JAGN1	ENST00000489724.2	c.*356G>A		3_prime_UTR_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1547 AN: 152174 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0350

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00268 AC: 672 AN: 250994 Hom.: 12 AF XY: 0.00195 AC XY: 264 AN XY: 135660

Gnomad AFR exome AF: 0.0366

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00110 AC: 1610 AN: 1461890 Hom.: 27 Cov.: 34 AF XY: 0.000986 AC XY: 717 AN XY: 727246

Gnomad4 AFR exome AF: 0.0379

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.0102 AC: 1553 AN: 152292 Hom.: 30 Cov.: 32 AF XY: 0.0101 AC XY: 753 AN XY: 74452

Gnomad4 AFR AF: 0.0351

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00173 Hom.: 5

Bravo AF: 0.0118

ESP6500AA AF: 0.0345 AC: 152

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00334 AC: 406

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive severe congenital neutropenia due to JAGN1 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.0094	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.070	N;.
REVEL	Benign	0.19
Sift	Benign	0.70	T;.
Sift4G	Benign	0.68	T;.
Polyphen		0.98	D;D
Vest4		0.12
MVP		0.76
MPC		0.21
ClinPred		0.031	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.76

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: rs61746084; hg19: chr3-9934912;