19-17834908-C-T

Variant names:

• chr19-17834908-C-T
• rs1057520020
• NM_000215.4:c.2143G>A

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.2143G>A​(p.Val715Ile) 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. 16/22 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: Not reported in ClinVar
• Conservation: PhyloP100: 0.306
• Publications: 4 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=0.20553249).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000215.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	NM_000215.4	MANE Select	c.2143G>A	p.Val715Ile	missense	Exon 16 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.2143G>A	p.Val715Ile	missense	Exon 16 of 24	NP_001427368.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	ENST00000458235.7	TSL:5 MANE Select	c.2143G>A	p.Val715Ile	missense	Exon 16 of 24	ENSP00000391676.1
	JAK3	ENST00000527670.5	TSL:1	c.2143G>A	p.Val715Ile	missense	Exon 15 of 23	ENSP00000432511.1
	JAK3	ENST00000534444.1	TSL:1	c.2143G>A	p.Val715Ile	missense	Exon 16 of 23	ENSP00000436421.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.31
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.67	N
REVEL	Benign	0.049
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.013	D
Polyphen		0.056	B
Vest4		0.23
MutPred		0.56		Loss of glycosylation at S720 (P = 0.1812)
MVP		0.41
MPC		0.61
ClinPred		0.23	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.51
Mutation Taster		=99/1	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057520020; hg19: chr19-17945717; COSMIC: COSV71686208;