rs3212723

chr19-17843406-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000215.4(JAK3):c.394C>A(p.Pro132Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,595,588 control chromosomes in the GnomAD database, including 321 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.025 (169 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (152 hom.)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Benign reviewed by expert panel P:2 B:6 O:1
• Conservation: PhyloP100: 1.91

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022203922).
• BP6: Variant 19-17843406-G-T is Benign according to our data. Variant chr19-17843406-G-T is described in ClinVar as [Benign]. Clinvar id is 134580.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-17843406-G-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0837 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK3	NM_000215.4	c.394C>A	p.Pro132Thr	missense_variant	4/24	ENST00000458235.7
JAK3	XM_047438786.1	c.394C>A	p.Pro132Thr	missense_variant	4/24
JAK3	XM_011527991.3	c.394C>A	p.Pro132Thr	missense_variant	4/14
JAK3	XR_007066796.1	n.444C>A		non_coding_transcript_exon_variant	4/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK3	ENST00000458235.7	c.394C>A	p.Pro132Thr	missense_variant	4/24	5	NM_000215.4	P1

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3736 AN: 152174 Hom.: 169 Cov.: 32

Gnomad AFR AF: 0.0861

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00877

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00617 AC: 1363 AN: 220906 Hom.: 51 AF XY: 0.00409 AC XY: 492 AN XY: 120248

Gnomad AFR exome AF: 0.0919

Gnomad AMR exome AF: 0.00415

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000287

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000718

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00244 AC: 3526 AN: 1443296 Hom.: 152 Cov.: 32 AF XY: 0.00207 AC XY: 1487 AN XY: 716650

Gnomad4 AFR exome AF: 0.0887

Gnomad4 AMR exome AF: 0.00476

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000238

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000489

Gnomad4 OTH exome AF: 0.00527

GnomAD4 genome AF: 0.0246 AC: 3747 AN: 152292 Hom.: 169 Cov.: 32 AF XY: 0.0233 AC XY: 1734 AN XY: 74466

Gnomad4 AFR AF: 0.0861

Gnomad4 AMR AF: 0.00875

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00749 Hom.: 34

Bravo AF: 0.0283

ESP6500AA AF: 0.0877 AC: 386

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00701 AC: 845

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

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

Revision: reviewed by expert panel

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 29, 2021	- -
Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jan 23, 2024	The c.394C>A (NM_000215.4) variant in JAK3 is a missense variant predicted to cause substitution of Proline by Threonine at amino acid 132 (p.Pro132Thr). The filtering allele frequency (the lower threshold of the 95% CI of 6500/74518) of the c.394C>A variant in JAK3 is 0.08599 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, and therefore meets this criterion (BA1). Furthermore, 321 adult homozygous were described in GnomAD v.2.1.1, meeting BS2_Supporting criteria. In summary, this variant meets the criteria to be classified as 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: BA1 and BS2_Supporting (VCEP specifications version 1.0). -

not specified Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Acute megakaryoblastic leukemia Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Lymphoblastic leukemia, acute, with lymphomatous features Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

JAK3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as 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	Benign	0.12
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	19
Dann	Benign	0.91
DEOGEN2	Benign	0.19	T;T;.
Eigen	Benign	0.090
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.60	T;.;T
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	0.97	P;P;P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.092
Sift	Benign	0.40	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.22	B;B;B
Vest4		0.42
MVP		0.73
MPC		1.1
ClinPred		0.025	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.63

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: rs3212723; hg19: chr19-17954215; COSMIC: COSV71686852; COSMIC: COSV71686852;