rs145751599

chr19-17839566-C-Gchr19-17839566-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000215.4(JAK3):c.1352G>C(p.Arg451Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,457,702 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R451Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.677

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK3	NM_000215.4	c.1352G>C	p.Arg451Pro	missense_variant	10/24	ENST00000458235.7
JAK3	XM_047438786.1	c.1352G>C	p.Arg451Pro	missense_variant	10/24
JAK3	XM_011527991.3	c.1352G>C	p.Arg451Pro	missense_variant	10/14
JAK3	XR_007066796.1	n.1402G>C		non_coding_transcript_exon_variant	10/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK3	ENST00000458235.7	c.1352G>C	p.Arg451Pro	missense_variant	10/24	5	NM_000215.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1457702 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724616

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;D;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.85	T;.;T
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M;M;M
MutationTaster	Benign	0.67	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.024	D;D;D
Sift4G	Uncertain	0.051	T;T;D
Polyphen		0.14	B;B;D
Vest4		0.77
MutPred		0.54		Gain of catalytic residue at R451 (P = 0.1065);Gain of catalytic residue at R451 (P = 0.1065);Gain of catalytic residue at R451 (P = 0.1065);
MVP		0.79
MPC		1.1
ClinPred		0.90	D
GERP RS		2.6
Varity_R		0.72
gMVP		0.87

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: chr19-17950375;