rs1057519770

Variant names:

• chr19-17843825-A-G
• rs1057519770
• NM_000215.4:c.260T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

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. 15/22 in silico tools predict 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: 32)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.42
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• T-B+ severe combined immunodeficiency due to JAK3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24919617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.260T>C	p.Ile87Thr	missense_variant	Exon 3 of 24	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.260T>C	p.Ile87Thr	missense_variant	Exon 3 of 24		NP_001427368.1
JAK3	XM_011527991.3	c.260T>C	p.Ile87Thr	missense_variant	Exon 3 of 14		XP_011526293.2
JAK3	XR_007066796.1	n.310T>C		non_coding_transcript_exon_variant	Exon 3 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.260T>C	p.Ile87Thr	missense_variant	Exon 3 of 24	5	NM_000215.4	ENSP00000391676.1

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

Dec 26, 2014

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Leukemoid reaction Pathogenic:1

May 13, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
PhyloP100		8.4
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
Mutation Taster		=17/83	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057519770; hg19: chr19-17954634; COSMIC: COSV71686015;