Genetic Variant JAK3:p.Ser580Trp (chr19-17837176-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000215.4(JAK3):c.1739C>G(p.Ser580Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S580L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

JAK3
NM_000215.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.18

Publications

0 publications found

Variant links:

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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

JAK3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.881

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.1739C>G	p.Ser580Trp	missense	Exon 13 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.1739C>G	p.Ser580Trp	missense	Exon 13 of 24	NP_001427368.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
JAK3	ENST00000458235.7	TSL:5 MANE Select	c.1739C>G	p.Ser580Trp	missense	Exon 13 of 24	ENSP00000391676.1	P52333-1
JAK3	ENST00000527670.5	TSL:1	c.1739C>G	p.Ser580Trp	missense	Exon 12 of 23	ENSP00000432511.1	P52333-1
JAK3	ENST00000534444.1	TSL:1	c.1739C>G	p.Ser580Trp	missense	Exon 13 of 23	ENSP00000436421.1	P52333-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1421106

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703010

African (AFR)

AF:

0.00

AC:

AN:

32606

American (AMR)

AF:

0.00

AC:

AN:

39274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25394

East Asian (EAS)

AF:

0.00

AC:

AN:

37704

South Asian (SAS)

AF:

0.00

AC:

AN:

80750

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50648

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4730

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091154

Other (OTH)

AF:

0.00

AC:

AN:

58846

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

T-B+ severe combined immunodeficiency due to JAK3 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.23

MutationAssessor

Pathogenic

3.6

PhyloP100

9.2

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-6.3

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.65

MutPred

0.59

Loss of disorder (P = 0.0526)

MVP

0.76

MPC

1.6

ClinPred

1.0

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.49

Mutation Taster

=20/80

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over