19-17832563-T-G

Variant names:

• chr19-17832563-T-G
• rs3179893
• NM_000215.4:c.2636A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000215.4(JAK3):​c.2636A>C​(p.His879Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. H879R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.84
• 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.2636A>C	p.His879Pro	missense_variant	Exon 19 of 24	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.2636A>C	p.His879Pro	missense_variant	Exon 19 of 24		NP_001427368.1
JAK3	XR_007066796.1	n.2686A>C		non_coding_transcript_exon_variant	Exon 19 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.2636A>C	p.His879Pro	missense_variant	Exon 19 of 24	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.77	D;D;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;.;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.4	L;L;L
PhyloP100		5.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.018	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.87	P;P;D
Vest4		0.53
MutPred		0.55		Loss of MoRF binding (P = 0.0924);Loss of MoRF binding (P = 0.0924);Loss of MoRF binding (P = 0.0924);
MVP		0.94
MPC		1.6
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.92
gMVP		0.95
Mutation Taster		=19/81	disease causing

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: rs3179893; hg19: chr19-17943372;