rs749481781

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_000215.4(JAK3):c.2680+3G>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

JAK3
NM_000215.4 splice_donor_region, intron

Scores

Splicing: ADA: 0.3596

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 0.113

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-17832516-C-G is Pathogenic according to our data. Variant chr19-17832516-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 328503.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}. Variant chr19-17832516-C-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
JAK3	NM_000215.4 linkuse as main transcript	c.2680+3G>C	splice_donor_region_variant, intron_variant		ENST00000458235.7
JAK3	XM_047438786.1 linkuse as main transcript	c.2680+3G>C	splice_donor_region_variant, intron_variant
JAK3	XR_007066796.1 linkuse as main transcript	n.2733G>C	non_coding_transcript_exon_variant	19/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK3	ENST00000458235.7 linkuse as main transcript	c.2680+3G>C		splice_donor_region_variant, intron_variant		5	NM_000215.4	P1	P52333-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251382

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135886

show subpopulations

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727232

show subpopulations

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:

0.0000342

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000227

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	This sequence change falls in intron 19 of the JAK3 gene. It does not directly change the encoded amino acid sequence of the JAK3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs749481781, gnomAD 0.003%). This variant has been observed in individual(s) with severe combined immunodeficiency and/or partial JAK3 deficiency (PMID: 11668621, 11781709). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as intron 18 G2775(+3)C or IVS18+3G>C. ClinVar contains an entry for this variant (Variation ID: 328503). Studies have shown that this variant alters JAK3 gene expression (PMID: 11781709). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in retention of 87 nucleotides from intron 19 and introduces a premature termination codon (PMID: 11781709). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 06, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The JAK3 c.2680+3G>C variant has been reported in three studies, all of which describe the same two siblings with severe combined immune deficiency who carry the variant in a compound heterozygous state (Mella et al. 2001; Notarangelo et al. 2001; Frucht et al. 2001). One sibling presented with a very severe phenotype and the other with a mild, nearly normal phenotype, but both siblings were found to carry the c.2680+3G>C variant along with an initiator codon variant. The c.2680+3G>C variant was also found in a heterozygous state in their unaffected mother (Frucht et al. 2001). The variant was absent from 100 healthy control chromosomes and is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on one allele, so the variant is presumed to be rare. Analysis of cDNA from the sibling with the mild phenotype showed that the c.2680+3G>C variant results in both normally spliced exon 18 and a product containing an intronic sequence that leads to a premature termination of the protein (Frucht et al. 2001). Based on the evidence, the c.2680+3G>C variant is classified as a variant of unknown significance but suspicious for pathogenicity for severe combined immune deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

Cadd

Benign

6.8

Dann

Benign

0.51

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.36

dbscSNV1_RF

Benign

0.44

SpliceAI score (max)

0.70

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.33

Position offset: -29

DS_DL_spliceai

0.70

Position offset: 3

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over