NM_000215.4:c.2773C>A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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:3 B:6
• 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: Likely_benign. The variant received -4 ACMG points.

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

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>A	p.Arg925Ser	missense	Exon 20 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.2773C>A	p.Arg925Ser	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>A	p.Arg925Ser	missense	Exon 20 of 24	ENSP00000391676.1
	JAK3	ENST00000527670.5	TSL:1	c.2773C>A	p.Arg925Ser	missense	Exon 19 of 23	ENSP00000432511.1
	JAK3	ENST00000534444.1	TSL:1	c.2773C>A	p.Arg925Ser	missense	Exon 20 of 23	ENSP00000436421.1

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

GnomAD2 exomes AF: 0.00104 AC: 247 AN: 237354 AF XY: 0.00101

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 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

African (AFR) AF: 0.000179 AC: 6 AN: 33432

American (AMR) AF: 0.00276 AC: 122 AN: 44262

Ashkenazi Jewish (ASJ) AF: 0.00580 AC: 151 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85874

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

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5754

European-Non Finnish (NFE) AF: 0.000409 AC: 454 AN: 1111018

Other (OTH) AF: 0.00186 AC: 112 AN: 60232

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

African (AFR) AF: 0.000289 AC: 12 AN: 41572

American (AMR) AF: 0.00497 AC: 76 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68028

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00115 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

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	4	T-B+ severe combined immunodeficiency due to JAK3 deficiency (6)
1	1	-	not provided (2)
-	-	1	JAK3-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.52
Sift	Benign	0.046	D
Sift4G	Benign	0.20	T
Polyphen		0.27	B
Vest4		0.55
MVP		0.92
MPC		0.93
ClinPred		0.018	T
GERP RS		1.6
Varity_R		0.57
gMVP		0.94
Mutation Taster		=38/62	disease causing (ClinVar)

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: COSV71685856;