19-17831706-G-T

Position:

• chr19-17831706-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The NM_000215.4(JAK3):c.2773C>A (p.Arg925Ser) missense variant has a popmax filtering allele frequency in gnomAD v2.1.1 is 0.002278 (based on 94/34558 alleles in the Latino/Admixed American population), which is above the ClinGen SCID VCEP threshold of >0.00100 (BS1). To our knowledge, the variant has not been reported in a SCID patient in the literature. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive T-B+ SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1 (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA9301512/MONDO:0010938/121

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (1 hom.)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:2 B:6
• Conservation: PhyloP100: 1.38

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 Likely_benign. Variant got -4 ACMG points.

• BS1: 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.2773C>A	p.Arg925Ser	missense_variant	20/24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1	c.2773C>A	p.Arg925Ser	missense_variant	20/24		XP_047294742.1
JAK3	XR_007066796.1	n.*16C>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.2773C>A	p.Arg925Ser	missense_variant	20/24	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00104 AC: 247 AN: 237354 Hom.: 0 AF XY: 0.00101 AC XY: 132 AN XY: 130328

Gnomad AFR exome AF: 0.000281

Gnomad AMR exome AF: 0.00273

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000746

Gnomad OTH exome AF: 0.00223

GnomAD4 exome AF: 0.000589 AC: 859 AN: 1458250 Hom.: 1 Cov.: 33 AF XY: 0.000586 AC XY: 425 AN XY: 725374

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00276

Gnomad4 ASJ exome AF: 0.00580

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.000409

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.00106 AC: 161 AN: 152300 Hom.: 1 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74460

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00166 Hom.: 0

Bravo AF: 0.00123

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000937 AC: 8

ExAC AF: 0.000686 AC: 83

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Uncertain:2 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency Uncertain:1 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	The NM_000215.4(JAK3):c.2773C>A (p.Arg925Ser) missense variant has a popmax filtering allele frequency in gnomAD v2.1.1 is 0.002278 (based on 94/34558 alleles in the Latino/Admixed American population), which is above the ClinGen SCID VCEP threshold of >0.00100 (BS1). To our knowledge, the variant has not been reported in a SCID patient in the literature. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive T-B+ SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1 (VCEP specifications version 1). -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 12, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2015	The R925S variant in the JAK3 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project and the 1000 Genomes Project Consortium report R925S was observed in approximately 0.1-0.2% of alleles from individuals of European background, indicating it may be a rare variant in this population. The variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and this substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. However, functional studies have shown that R925S impairs both interaction with STAT5 and JAK3 and STAT5 phosphorylation (de Martino et al., 2013). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 15, 2024

Variant summary: JAK3 c.2773C>A (p.Arg925Ser) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00063 in 1610550 control chromosomes, including 2 homozygotes, and predominantly at a frequency of 0.0033 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in JAK3 causing Severe Combined Immunodeficiency phenotype (0.00094), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.2773C>A in individuals affected with Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 418267). Based on the evidence outlined above, the variant was classified as likely benign. -

JAK3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 03, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.73	T;.;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.026	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.81	L;L;L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.046	D;D;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.27	B;B;P
Vest4		0.55
MVP		0.92
MPC		0.93
ClinPred		0.018	T
GERP RS		1.6
Varity_R		0.57
gMVP		0.94

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: rs149452625; hg19: chr19-17942515; COSMIC: COSV71685856;