19-17834962-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000215.4(JAK3):c.2089C>G(p.Arg697Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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. R697Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.138

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 2 ACMG points.

• PM1: In a domain Protein kinase 1 (size 260) in uniprot entity JAK3_HUMAN there are 21 pathogenic changes around while only 8 benign (72%) in NM_000215.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.108475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK3	NM_000215.4	c.2089C>G	p.Arg697Gly	missense_variant	16/24	ENST00000458235.7
JAK3	XM_047438786.1	c.2089C>G	p.Arg697Gly	missense_variant	16/24
JAK3	XR_007066796.1	n.2139C>G		non_coding_transcript_exon_variant	16/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK3	ENST00000458235.7	c.2089C>G	p.Arg697Gly	missense_variant	16/24	5	NM_000215.4	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	Benign	0.066
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	15
Dann	Benign	0.93
DEOGEN2	Uncertain	0.48	T;T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.31	T;.;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.97	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.23
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.035
MutPred		0.53		Loss of solvent accessibility (P = 0.0769);Loss of solvent accessibility (P = 0.0769);Loss of solvent accessibility (P = 0.0769);
MVP		0.67
MPC		0.62
ClinPred		0.044	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.060
gMVP		0.65

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: chr19-17945771;