3-9893228-G-T

Variant names:

• chr3-9893228-G-T
• rs61746084
• NM_032492.4:c.403G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032492.4(JAGN1):​c.403G>T​(p.Ala135Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A135T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAGN1 NM_032492.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.91
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAGN1	NM_032492.4	c.403G>T	p.Ala135Ser	missense_variant	Exon 2 of 2	ENST00000647897.1	NP_115881.3
JAGN1	NM_001363890.1	c.241G>T	p.Ala81Ser	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	c.403G>T	p.Ala135Ser	missense_variant	Exon 2 of 2		NM_032492.4	ENSP00000496942.1
JAGN1	ENST00000489724.2	c.*356G>T		3_prime_UTR_variant	Exon 2 of 2	3		ENSP00000497724.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250994 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		4.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.19	N;.
REVEL	Benign	0.20
Sift	Benign	0.39	T;.
Sift4G	Benign	0.36	T;.
Polyphen		0.23	B;B
Vest4		0.11
MutPred		0.77		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.69
MPC		0.20
ClinPred		0.86	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.70
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs61746084; hg19: chr3-9934912;