19-17844395-G-A

Position:

• chr19-17844395-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000215.4(JAK3):​c.23C>T​(p.Thr8Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000733 in 1,611,570 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00075 (0 hom.)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:2
• Conservation: PhyloP100: 2.89

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a region_of_interest Interaction with cytokine/interferon/growth hormone receptors (size 222) in uniprot entity JAK3_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000215.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12151155).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK3	NM_000215.4	c.23C>T	p.Thr8Met	missense_variant	2/24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1	c.23C>T	p.Thr8Met	missense_variant	2/24		XP_047294742.1
JAK3	XM_011527991.3	c.23C>T	p.Thr8Met	missense_variant	2/14		XP_011526293.2
JAK3	XR_007066796.1	n.73C>T		non_coding_transcript_exon_variant	2/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.23C>T	p.Thr8Met	missense_variant	2/24	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152162 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000560 AC: 136 AN: 242704 Hom.: 0 AF XY: 0.000536 AC XY: 71 AN XY: 132506

Gnomad AFR exome AF: 0.000332

Gnomad AMR exome AF: 0.000819

Gnomad ASJ exome AF: 0.000509

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000479

Gnomad NFE exome AF: 0.000885

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000754 AC: 1100 AN: 1459292 Hom.: 0 Cov.: 32 AF XY: 0.000737 AC XY: 535 AN XY: 725812

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000808

Gnomad4 ASJ exome AF: 0.000307

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000383

Gnomad4 NFE exome AF: 0.000887

Gnomad4 OTH exome AF: 0.000928

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152278 Hom.: 0 Cov.: 31 AF XY: 0.000510 AC XY: 38 AN XY: 74464

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000834 Hom.: 0

Bravo AF: 0.000529

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000819 AC: 7

ExAC AF: 0.000595 AC: 72

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency Uncertain:3 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 8 of the JAK3 protein (p.Thr8Met). This variant is present in population databases (rs145500023, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with JAK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 134575). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 30, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 06-27-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.71	T;.;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	0.69	N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.21
MVP		0.79
MPC		1.4
ClinPred		0.029	T
GERP RS		4.2
Varity_R		0.036
gMVP		0.51

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: rs145500023; hg19: chr19-17955204;