19-17838329-C-G

Position:

• chr19-17838329-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000215.4(JAK3):​c.1503G>C​(p.Gln501His) 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.

• Frequency: Genomes: not found (cov: 31)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.495

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10577032).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK3	NM_000215.4	c.1503G>C	p.Gln501His	missense_variant	11/24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1	c.1503G>C	p.Gln501His	missense_variant	11/24		XP_047294742.1
JAK3	XM_011527991.3	c.1503G>C	p.Gln501His	missense_variant	11/14		XP_011526293.2
JAK3	XR_007066796.1	n.1553G>C		non_coding_transcript_exon_variant	11/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.1503G>C	p.Gln501His	missense_variant	11/24	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	1.5
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T;T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.44	T;.;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.57	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.0	B;B;P
Vest4		0.065
MutPred		0.15		Gain of glycosylation at S497 (P = 0.1311);Gain of glycosylation at S497 (P = 0.1311);Gain of glycosylation at S497 (P = 0.1311);
MVP		0.70
MPC		0.45
ClinPred		0.12	T
GERP RS		1.2
Varity_R		0.054
gMVP		0.25

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: rs201283129; hg19: chr19-17949138; COSMIC: COSV71685911; COSMIC: COSV71685911;