19-17834989-T-G

Position:

• chr19-17834989-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000215.4(JAK3):​c.2062A>C​(p.Ile688Leu) 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.73

Genes affected

JAK3 (HGNC:6193): (Janus kinase 3) The protein encoded by this gene is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction. It is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. Mutations in this gene are associated with autosomal SCID (severe combined immunodeficiency disease). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain Protein kinase 1 (size 260) in uniprot entity JAK3_HUMAN there are 11 pathogenic changes around while only 3 benign (79%) in NM_000215.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK3	NM_000215.4	c.2062A>C	p.Ile688Leu	missense_variant	16/24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1	c.2062A>C	p.Ile688Leu	missense_variant	16/24		XP_047294742.1
JAK3	XR_007066796.1	n.2112A>C		non_coding_transcript_exon_variant	16/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.2062A>C	p.Ile688Leu	missense_variant	16/24	5	NM_000215.4	ENSP00000391676	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N;N;N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.018	D;D;D
Sift4G	Uncertain	0.032	D;D;D
Polyphen		0.96	D;D;P
Vest4		0.53
MutPred		0.61		Gain of catalytic residue at I688 (P = 0.0089);Gain of catalytic residue at I688 (P = 0.0089);Gain of catalytic residue at I688 (P = 0.0089);
MVP		0.74
MPC		1.0
ClinPred		0.91	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-17945798;