rs143586866

chr19-17843438-C-Gchr19-17843438-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000215.4(JAK3):c.362G>C(p.Arg121Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R121H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1612857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK3	NM_000215.4	c.362G>C	p.Arg121Pro	missense_variant	4/24	ENST00000458235.7
JAK3	XM_047438786.1	c.362G>C	p.Arg121Pro	missense_variant	4/24
JAK3	XM_011527991.3	c.362G>C	p.Arg121Pro	missense_variant	4/14
JAK3	XR_007066796.1	n.412G>C		non_coding_transcript_exon_variant	4/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK3	ENST00000458235.7	c.362G>C	p.Arg121Pro	missense_variant	4/24	5	NM_000215.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000440 AC: 1 AN: 227166 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 123464

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000990

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447616 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 719122

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: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Benign	0.26	T;T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.71	T;.;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.94	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.25
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.32
MutPred		0.51		Gain of ubiquitination at K122 (P = 0.0741);Gain of ubiquitination at K122 (P = 0.0741);Gain of ubiquitination at K122 (P = 0.0741);
MVP		0.92
MPC		0.70
ClinPred		0.10	T
GERP RS		2.5
Varity_R		0.29
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs143586866; hg19: chr19-17954247;