19-17837171-G-C

Variant names:

• chr19-17837171-G-C
• rs193922361
• NM_000215.4:c.1744C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000215.4(JAK3):​c.1744C>G​(p.Arg582Gly) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R582W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.53
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-17837171-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 36415.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.40778974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.1744C>G	p.Arg582Gly	missense_variant	Exon 13 of 24	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.1744C>G	p.Arg582Gly	missense_variant	Exon 13 of 24		NP_001427368.1
JAK3	XM_011527991.3	c.1744C>G	p.Arg582Gly	missense_variant	Exon 13 of 14		XP_011526293.2
JAK3	XR_007066796.1	n.1794C>G		non_coding_transcript_exon_variant	Exon 13 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.1744C>G	p.Arg582Gly	missense_variant	Exon 13 of 24	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;D;.
Eigen	Benign	-0.055
Eigen_PC	Benign	0.0050
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D;.;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.3	M;M;M
PhyloP100		3.5
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.019	D;D;D
Sift4G	Uncertain	0.052	T;T;D
Vest4		0.22
ClinPred		0.95	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.22
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs193922361; hg19: chr19-17947980;