chr19-17843147-C-G

Position:

• chr19-17843147-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000215.4(JAK3):​c.446G>C​(p.Arg149Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.663

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK3	NM_000215.4	c.446G>C	p.Arg149Pro	missense_variant	5/24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1	c.446G>C	p.Arg149Pro	missense_variant	5/24		XP_047294742.1
JAK3	XM_011527991.3	c.446G>C	p.Arg149Pro	missense_variant	5/14		XP_011526293.2
JAK3	XR_007066796.1	n.496G>C		non_coding_transcript_exon_variant	5/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.446G>C	p.Arg149Pro	missense_variant	5/24	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454904 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723918

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 22, 2018

This variant has not been reported in the literature in individuals with JAK3-related disease. This sequence change replaces arginine with proline at codon 149 of the JAK3 protein (p.Arg149Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.0056	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.71	T;.;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.6	M;M;M
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.98	D;D;D
Vest4		0.66
MutPred		0.53		Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);
MVP		0.85
MPC		1.4
ClinPred		0.76	D
GERP RS		-0.069
Varity_R		0.31
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: -19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs774941503; hg19: chr19-17953956;