rs1424732031

Variant names:

• chr19-17830211-AG-A
• rs1424732031
• NM_000215.4:c.3103delC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000215.4(JAK3):​c.3103delC​(p.Leu1035CysfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000385 in 1,557,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: JAK3 NM_000215.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 0.158
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-17830211-AG-A is Pathogenic according to our data. Variant chr19-17830211-AG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 523047.

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.3103delC	p.Leu1035CysfsTer3	frameshift	Exon 23 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.3103delC	p.Leu1035CysfsTer3	frameshift	Exon 23 of 24	NP_001427368.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	ENST00000458235.7	TSL:5 MANE Select	c.3103delC	p.Leu1035CysfsTer3	frameshift	Exon 23 of 24	ENSP00000391676.1	P52333-1
	JAK3	ENST00000527670.5	TSL:1	c.3103delC	p.Leu1035CysfsTer3	frameshift	Exon 22 of 23	ENSP00000432511.1	P52333-1
	JAK3	ENST00000534444.1	TSL:1	c.3103delC	p.Leu1035CysfsTer3	frameshift	Exon 23 of 23	ENSP00000436421.1	P52333-2

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000728

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1405870 Hom.: 0 Cov.: 32 AF XY: 0.00000288 AC XY: 2 AN XY: 695618

African (AFR) AF: 0.00 AC: 0 AN: 31862

American (AMR) AF: 0.00 AC: 0 AN: 39006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24688

East Asian (EAS) AF: 0.00 AC: 0 AN: 36540

South Asian (SAS) AF: 0.00 AC: 0 AN: 80804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4764

European-Non Finnish (NFE) AF: 0.00000277 AC: 3 AN: 1082582

Other (OTH) AF: 0.00 AC: 0 AN: 57600

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151160 Hom.: 0 Cov.: 32 AF XY: 0.0000406 AC XY: 3 AN XY: 73838

African (AFR) AF: 0.0000728 AC: 3 AN: 41200

American (AMR) AF: 0.00 AC: 0 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5078

South Asian (SAS) AF: 0.00 AC: 0 AN: 4750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67780

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	T-B+ severe combined immunodeficiency due to JAK3 deficiency (2)
1	-	-	Severe combined immunodeficiency disease (1)
-	1	-	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
Mutation Taster		=12/188	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1424732031; hg19: chr19-17941020;