3-9890744-CGAGCGGCCGGCACCGACGGCAGCGACTTTCAGCACCG-C

Position:

• chr3-9890744-CGAGCGGCCGGCACCGACGGCAGCGACTTTCAGCACCG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_032492.4(JAGN1):​c.24_60del​(p.Ala9SerfsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAGN1 NM_032492.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.41

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.958 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAGN1	NM_032492.4	c.24_60del	p.Ala9SerfsTer9	frameshift_variant	1/2	ENST00000647897.1	NP_115881.3
JAGN1	NM_001363890.1	c.-245_-209del		5_prime_UTR_variant	1/2		NP_001350819.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAGN1	ENST00000647897.1	c.24_60del	p.Ala9SerfsTer9	frameshift_variant	1/2		NM_032492.4	ENSP00000496942	P1
JAGN1	ENST00000489724.2	c.24_60del	p.Ala9SerfsTer9	frameshift_variant	1/2	3		ENSP00000497724

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 28, 2022

This sequence change creates a premature translational stop signal (p.Ala9Serfs*9) in the JAGN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 175 amino acid(s) of the JAGN1 protein. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant has not been reported in the literature in individuals affected with JAGN1-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-9932428;