rs35365817

Positions:

• chr3-9893069-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/19 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.58

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 -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 id is 475246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9893069-A-G is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAGN1	NM_032492.4	c.244A>G	p.Ile82Val	missense_variant	2/2	ENST00000647897.1	NP_115881.3
JAGN1	NM_001363890.1	c.82A>G	p.Ile28Val	missense_variant	2/2		NP_001350819.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAGN1	ENST00000647897.1	c.244A>G	p.Ile82Val	missense_variant	2/2		NM_032492.4	ENSP00000496942	P1
JAGN1	ENST00000489724.2	c.*197A>G		3_prime_UTR_variant	2/2	3		ENSP00000497724

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3461 AN: 152140 Hom.: 56 Cov.: 32

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

GnomAD3 exomes AF: 0.0224 AC: 5638 AN: 251454 Hom.: 87 AF XY: 0.0229 AC XY: 3116 AN XY: 135906

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 SAS exome AF: 0.00738

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.: 33 AF XY: 0.0313 AC XY: 22788 AN XY: 727226

Gnomad4 AFR exome AF: 0.00481

Gnomad4 AMR exome AF: 0.0172

Gnomad4 ASJ exome AF: 0.0179

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00792

Gnomad4 FIN exome AF: 0.0119

Gnomad4 NFE exome AF: 0.0379

Gnomad4 OTH exome AF: 0.0275

GnomAD4 genome AF: 0.0227 AC: 3461 AN: 152258 Hom.: 56 Cov.: 32 AF XY: 0.0213 AC XY: 1584 AN XY: 74452

Gnomad4 AFR AF: 0.00705

Gnomad4 AMR AF: 0.0234

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00892

Gnomad4 FIN AF: 0.0104

Gnomad4 NFE AF: 0.0365

Gnomad4 OTH AF: 0.0228

Alfa AF: 0.0334 Hom.: 163

Bravo AF: 0.0235

TwinsUK AF: 0.0343 AC: 127

ALSPAC AF: 0.0431 AC: 166

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.0349 AC: 300

ExAC AF: 0.0231 AC: 2810

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0402

EpiControl AF: 0.0385

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.31	T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.66	.;T
MetaRNN	Benign	0.0058	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.44	T
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	T
GERP RS		-0.0094
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.42

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: rs35365817; hg19: chr3-9934753; COSMIC: COSV99071988; COSMIC: COSV99071988;