rs1057519770

Positions:

• chr19-17843825-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

The NM_000215.4(JAK3):​c.260T>C​(p.Ile87Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.42

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 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
• PP5: Variant 19-17843825-A-G is Pathogenic according to our data. Variant chr19-17843825-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376116.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24919617). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK3	NM_000215.4	c.260T>C	p.Ile87Thr	missense_variant	3/24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1	c.260T>C	p.Ile87Thr	missense_variant	3/24		XP_047294742.1
JAK3	XM_011527991.3	c.260T>C	p.Ile87Thr	missense_variant	3/14		XP_011526293.2
JAK3	XR_007066796.1	n.310T>C		non_coding_transcript_exon_variant	3/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.260T>C	p.Ile87Thr	missense_variant	3/24	5	NM_000215.4	ENSP00000391676	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Acute megakaryoblastic leukemia Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Dec 26, 2014

- -

Leukemoid reaction Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	0.0066	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Benign	0.82
DEOGEN2	Benign	0.29	T;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.0034
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	T;.;T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.21	B;B;B
Vest4		0.34
MutPred		0.57		Gain of disorder (P = 0.0111);Gain of disorder (P = 0.0111);Gain of disorder (P = 0.0111);
MVP		0.58
MPC		0.77
ClinPred		0.46	T
GERP RS		5.1
Varity_R		0.18
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1057519770; hg19: chr19-17954634; COSMIC: COSV71686015; COSMIC: COSV71686015;