19-17844390-G-T

Variant names:

• chr19-17844390-G-T
• NM_000215.4:c.28C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000215.4(JAK3):​c.28C>A​(p.Leu10Met) 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. 12/21 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: Not reported in ClinVar
• Conservation: PhyloP100: 1.33

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a region_of_interest Interaction with cytokine/interferon/growth hormone receptors (size 222) in uniprot entity JAK3_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000215.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34610948).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.28C>A	p.Leu10Met	missense_variant	Exon 2 of 24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1	c.28C>A	p.Leu10Met	missense_variant	Exon 2 of 24		XP_047294742.1
JAK3	XM_011527991.3	c.28C>A	p.Leu10Met	missense_variant	Exon 2 of 14		XP_011526293.2
JAK3	XR_007066796.1	n.78C>A		non_coding_transcript_exon_variant	Exon 2 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.28C>A	p.Leu10Met	missense_variant	Exon 2 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	0.28
BayesDel_addAF	Benign	0.0082	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;.
Eigen	Benign	-0.014
Eigen_PC	Benign	-0.095
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	T;.;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Uncertain	-0.015	T
MutationAssessor	Benign	0.69	N;N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.38	N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.033	D;D;D
Sift4G	Uncertain	0.013	D;D;D
Polyphen		0.96	D;D;P
Vest4		0.37
MutPred		0.095		Gain of phosphorylation at T8 (P = 0.1098);Gain of phosphorylation at T8 (P = 0.1098);Gain of phosphorylation at T8 (P = 0.1098);
MVP		0.81
MPC		1.3
ClinPred		0.78	D
GERP RS		3.2
Varity_R		0.098
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-17955199; COSMIC: COSV71688251; COSMIC: COSV71688251;