NM_000215.4:c.3208-1172T>C

Variant names:

• chr19-17828082-A-G
• rs10419991
• NM_000215.4:c.3208-1172T>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.3208-1172T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.52 in 151,548 control chromosomes in the GnomAD database, including 21,542 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 0.52 (21542 hom., cov: 29)
• Consequence: JAK3 NM_000215.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.660
• Publications: 3 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 (AFR) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.3208-1172T>C		intron_variant	Intron 23 of 23	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.3208-1172T>C		intron_variant	Intron 23 of 23		NP_001427368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.3208-1172T>C		intron_variant	Intron 23 of 23	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes AF: 0.520 AC: 78744 AN: 151430 Hom.: 21524 Cov.: 29

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.471

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.528

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.520 AC: 78819 AN: 151548 Hom.: 21542 Cov.: 29 AF XY: 0.519 AC XY: 38426 AN XY: 74012

African (AFR) AF: 0.691 AC: 28547 AN: 41298

American (AMR) AF: 0.472 AC: 7171 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1976 AN: 3470

East Asian (EAS) AF: 0.476 AC: 2448 AN: 5144

South Asian (SAS) AF: 0.471 AC: 2261 AN: 4798

European-Finnish (FIN) AF: 0.442 AC: 4628 AN: 10480

Middle Eastern (MID) AF: 0.462 AC: 135 AN: 292

European-Non Finnish (NFE) AF: 0.446 AC: 30241 AN: 67876

Other (OTH) AF: 0.526 AC: 1107 AN: 2104

Alfa AF: 0.470 Hom.: 30455

Bravo AF: 0.529

Asia WGS AF: 0.462 AC: 1607 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.4
DANN	Benign	0.53
PhyloP100		0.66
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: rs10419991; hg19: chr19-17938891;