rs149452625

Variant names:

• chr19-17831706-G-A
• rs149452625
• NM_000215.4:c.2773C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-17831706-G-A
• chr19-17831706-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000215.4(JAK3):​c.2773C>T​(p.Arg925Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,610,432 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R925S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.38
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• T-B+ severe combined immunodeficiency due to JAK3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, Orphanet

ENSG00000297031 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000215.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	NM_000215.4	MANE Select	c.2773C>T	p.Arg925Cys	missense	Exon 20 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.2773C>T	p.Arg925Cys	missense	Exon 20 of 24	NP_001427368.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	ENST00000458235.7	TSL:5 MANE Select	c.2773C>T	p.Arg925Cys	missense	Exon 20 of 24	ENSP00000391676.1
	JAK3	ENST00000527670.5	TSL:1	c.2773C>T	p.Arg925Cys	missense	Exon 19 of 23	ENSP00000432511.1
	JAK3	ENST00000534444.1	TSL:1	c.2773C>T	p.Arg925Cys	missense	Exon 20 of 23	ENSP00000436421.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000135 AC: 32 AN: 237354 AF XY: 0.000130

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 FIN exome AF: 0.0000495

Gnomad NFE exome AF: 0.000293

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000215 AC: 313 AN: 1458250 Hom.: 1 Cov.: 33 AF XY: 0.000200 AC XY: 145 AN XY: 725374

African (AFR) AF: 0.0000299 AC: 1 AN: 33432

American (AMR) AF: 0.0000452 AC: 2 AN: 44262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 85874

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000271 AC: 301 AN: 1111018

Other (OTH) AF: 0.000116 AC: 7 AN: 60232

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74332

African (AFR) AF: 0.0000483 AC: 2 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000268 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000223 AC: 27

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	T-B+ severe combined immunodeficiency due to JAK3 deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.012	D
MutationAssessor	Benign	1.8	L
PhyloP100		1.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.67		Loss of MoRF binding (P = 0.0019)
MVP		0.91
MPC		1.6
ClinPred		0.29	T
GERP RS		1.6
Varity_R		0.35
gMVP		0.93
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs149452625; hg19: chr19-17942515; COSMIC: COSV71686003;