19-17831748-G-T

Variant names:

• chr19-17831748-G-T
• rs587778417
• NM_000215.4:c.2731C>A

Variant summary

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

The NM_000215.4(JAK3):​c.2731C>A​(p.Arg911Ser) 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 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. R911G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• 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

ENSG00000297031 (HGNC:):

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, 0.828

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	NM_000215.4	MANE Select	c.2731C>A	p.Arg911Ser	missense	Exon 20 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.2731C>A	p.Arg911Ser	missense	Exon 20 of 24	NP_001427368.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	ENST00000458235.7	TSL:5 MANE Select	c.2731C>A	p.Arg911Ser	missense	Exon 20 of 24	ENSP00000391676.1
	JAK3	ENST00000527670.5	TSL:1	c.2731C>A	p.Arg911Ser	missense	Exon 19 of 23	ENSP00000432511.1
	JAK3	ENST00000534444.1	TSL:1	c.2731C>A	p.Arg911Ser	missense	Exon 20 of 23	ENSP00000436421.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.011	D
MutationAssessor	Benign	0.40	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.072	T
Polyphen		0.095	B
Vest4		0.77
MutPred		0.64		Loss of MoRF binding (P = 0.0191)
MVP		0.97
MPC		1.3
ClinPred		0.94	D
GERP RS		0.35
Varity_R		0.74
gMVP		0.95
Mutation Taster		=41/59	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: rs587778417; hg19: chr19-17942557;