19-17836737-A-G

Variant names:

• chr19-17836737-A-G
• rs3212760
• NM_000215.4:c.1786+392T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000215.4(JAK3):​c.1786+392T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 432,382 control chromosomes in the GnomAD database, including 32,273 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (10452 hom., cov: 31)
  • Exomes 𝑓: 0.39 (21821 hom.)
• Consequence: JAK3 NM_000215.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.969
• Publications: 8 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	NM_000215.4	MANE Select	c.1786+392T>C		intron	N/A	NP_000206.2
	JAK3	NM_001440439.1		c.1786+392T>C		intron	N/A	NP_001427368.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	ENST00000458235.7	TSL:5 MANE Select	c.1786+392T>C		intron	N/A	ENSP00000391676.1
	JAK3	ENST00000527670.5	TSL:1	c.1786+392T>C		intron	N/A	ENSP00000432511.1
	JAK3	ENST00000534444.1	TSL:1	c.1786+392T>C		intron	N/A	ENSP00000436421.1

Frequencies

GnomAD3 genomes AF: 0.369 AC: 55918 AN: 151686 Hom.: 10437 Cov.: 31

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.394

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.564

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.369

GnomAD4 exome AF: 0.389 AC: 109068 AN: 280578 Hom.: 21821 Cov.: 0 AF XY: 0.390 AC XY: 57240 AN XY: 146644

African (AFR) AF: 0.322 AC: 2972 AN: 9220

American (AMR) AF: 0.291 AC: 3770 AN: 12940

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 3002 AN: 9640

East Asian (EAS) AF: 0.557 AC: 10811 AN: 19426

South Asian (SAS) AF: 0.398 AC: 16523 AN: 41470

European-Finnish (FIN) AF: 0.368 AC: 3333 AN: 9068

Middle Eastern (MID) AF: 0.365 AC: 423 AN: 1158

European-Non Finnish (NFE) AF: 0.385 AC: 62005 AN: 161246

Other (OTH) AF: 0.380 AC: 6229 AN: 16410

GnomAD4 genome AF: 0.369 AC: 55961 AN: 151804 Hom.: 10452 Cov.: 31 AF XY: 0.371 AC XY: 27483 AN XY: 74164

African (AFR) AF: 0.326 AC: 13496 AN: 41394

American (AMR) AF: 0.337 AC: 5135 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1095 AN: 3470

East Asian (EAS) AF: 0.565 AC: 2905 AN: 5146

South Asian (SAS) AF: 0.397 AC: 1910 AN: 4806

European-Finnish (FIN) AF: 0.379 AC: 3992 AN: 10542

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26191 AN: 67914

Other (OTH) AF: 0.365 AC: 766 AN: 2096

Alfa AF: 0.367 Hom.: 17772

Bravo AF: 0.362

Asia WGS AF: 0.423 AC: 1471 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.99
DANN	Benign	0.59
PhyloP100		-0.97
Mutation Taster		=100/0	polymorphism (auto)

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: rs3212760; hg19: chr19-17947546;