rs199773433

Positions:

• chr19-17844360-A-G
• chr19-17844360-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000215.4(JAK3):​c.58T>C​(p.Ser20Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.41

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]

JAK3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a region_of_interest Interaction with cytokine/interferon/growth hormone receptors (size 222) in uniprot entity JAK3_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000215.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33171773).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK3	NM_000215.4	c.58T>C	p.Ser20Pro	missense_variant	2/24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1	c.58T>C	p.Ser20Pro	missense_variant	2/24		XP_047294742.1
JAK3	XM_011527991.3	c.58T>C	p.Ser20Pro	missense_variant	2/14		XP_011526293.2
JAK3	XR_007066796.1	n.108T>C		non_coding_transcript_exon_variant	2/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.58T>C	p.Ser20Pro	missense_variant	2/24	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T;.;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Uncertain	0.091	D
MutationAssessor	Benign	0.69	N;N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.049	D;D;D
Polyphen		1.0	D;D;B
Vest4		0.36
MutPred		0.20		Gain of glycosylation at T21 (P = 0.0788);Gain of glycosylation at T21 (P = 0.0788);Gain of glycosylation at T21 (P = 0.0788);
MVP		0.92
MPC		0.66
ClinPred		0.78	D
GERP RS		5.3
Varity_R		0.38
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

LitVar

Other links and lift over

dbSNP: rs199773433; hg19: chr19-17955169; COSMIC: COSV71686215; COSMIC: COSV71686215;