rs144405201

Positions:

• chr19-17843898-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS2_Supporting BS1

This summary comes from the ClinGen Evidence Repository: The c.187A>G (NM_000215.4) variant in JAK3 is a missense variant predicted to cause the substitution of Isoleucine by Valine at amino acid 63 (p.Ile63Val).The popmax filtering allele frequency (the upper threshold of the 95% CI) of this variant is 0.00007135 (105/1179936 alleles) for European (non-Finnish) chromosomes by gnomAD v.4, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting; However, the highest MAF in the Ashkenazi Jewish population is 0.007061 (209/29600 alleles), which is above the SCID VCEP established threshold of >0.00100 for BS1. As this population is not known to have a higher prevalence, this is considered to meet BS1. One homozygote is described in gnomAD v.4 in the Ashkenazi Jewish population (BS2_Supporting).To our knowledge, this variant has not been reported in the literature in individuals affected with JAk3-SCID/related conditions or in functional studies.In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1 and BS2_Supporting (VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA9302225/MONDO:0010938/121

• Frequency:
  • Genomes: 𝑓 0.00024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: JAK3 NM_000215.4 missense, splice_region
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:2
• Conservation: PhyloP100: 3.59

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 Likely_benign. Variant got -5 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK3	NM_000215.4	c.187A>G	p.Ile63Val	missense_variant, splice_region_variant	3/24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1	c.187A>G	p.Ile63Val	missense_variant, splice_region_variant	3/24		XP_047294742.1
JAK3	XM_011527991.3	c.187A>G	p.Ile63Val	missense_variant, splice_region_variant	3/14		XP_011526293.2
JAK3	XR_007066796.1	n.237A>G		splice_region_variant, non_coding_transcript_exon_variant	3/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.187A>G	p.Ile63Val	missense_variant, splice_region_variant	3/24	5	NM_000215.4	ENSP00000391676	P1

Frequencies

GnomAD3 genomes AF: 0.000244 AC: 37 AN: 151948 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000347 AC: 87 AN: 250598 Hom.: 0 AF XY: 0.000339 AC XY: 46 AN XY: 135646

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00667

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000232 AC: 339 AN: 1461508 Hom.: 0 Cov.: 33 AF XY: 0.000232 AC XY: 169 AN XY: 727062

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00704

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000244 AC: 37 AN: 151948 Hom.: 1 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74222

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000960

Alfa AF: 0.000422 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000321 AC: 39

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jan 23, 2024	The c.187A>G (NM_000215.4) variant in JAK3 is a missense variant predicted to cause the substitution of Isoleucine by Valine at amino acid 63 (p.Ile63Val). The popmax filtering allele frequency (the upper threshold of the 95% CI) of this variant is 0.00007135 (105/1179936 alleles) for European (non-Finnish) chromosomes by gnomAD v.4, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting; However, the highest MAF in the Ashkenazi Jewish population is 0.007061 (209/29600 alleles), which is above the SCID VCEP established threshold of >0.00100 for BS1. As this population is not known to have a higher prevalence, this is considered to meet BS1. One homozygote is described in gnomAD v.4 in the Ashkenazi Jewish population (BS2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with JAk3-SCID/related conditions or in functional studies. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1 and BS2_Supporting (VCEP specifications version 1.0). -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jul 30, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T;.
Eigen	Benign	0.065
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;.;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.0	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.65	N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.96	D;D;P
Vest4		0.20
MVP		0.65
MPC		0.51
ClinPred		0.032	T
GERP RS		5.1
Varity_R		0.13
gMVP		0.50

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: rs144405201; hg19: chr19-17954707;