rs1122385

Variant names:

• chr19-17831561-T-C
• rs1122385
• NM_000215.4:c.2805+113A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000215.4(JAK3):​c.2805+113A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,493,028 control chromosomes in the GnomAD database, including 92,208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13305 hom., cov: 28)
  • Exomes 𝑓: 0.34 (78903 hom.)
• Consequence: JAK3 NM_000215.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.79
• 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

ENSG00000297031 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 19-17831561-T-C is Benign according to our data. Variant chr19-17831561-T-C is described in ClinVar as Benign. ClinVar VariationId is 1258955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.2805+113A>G		intron_variant	Intron 20 of 23	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.2805+113A>G		intron_variant	Intron 20 of 23		NP_001427368.1
JAK3	XR_007066796.1	n.*161A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.2805+113A>G		intron_variant	Intron 20 of 23	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61043 AN: 149714 Hom.: 13266 Cov.: 28

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.380

GnomAD4 exome AF: 0.337 AC: 453143 AN: 1343196 Hom.: 78903 Cov.: 25 AF XY: 0.338 AC XY: 223894 AN XY: 661790

African (AFR) AF: 0.567 AC: 17457 AN: 30762

American (AMR) AF: 0.499 AC: 17497 AN: 35048

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 6514 AN: 24180

East Asian (EAS) AF: 0.435 AC: 15533 AN: 35690

South Asian (SAS) AF: 0.410 AC: 32256 AN: 78594

European-Finnish (FIN) AF: 0.335 AC: 11983 AN: 35750

Middle Eastern (MID) AF: 0.350 AC: 1376 AN: 3934

European-Non Finnish (NFE) AF: 0.317 AC: 330377 AN: 1043196

Other (OTH) AF: 0.360 AC: 20150 AN: 56042

GnomAD4 genome AF: 0.408 AC: 61146 AN: 149832 Hom.: 13305 Cov.: 28 AF XY: 0.406 AC XY: 29653 AN XY: 72968

African (AFR) AF: 0.564 AC: 22942 AN: 40704

American (AMR) AF: 0.430 AC: 6474 AN: 15064

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 911 AN: 3448

East Asian (EAS) AF: 0.459 AC: 2271 AN: 4950

South Asian (SAS) AF: 0.426 AC: 2007 AN: 4716

European-Finnish (FIN) AF: 0.349 AC: 3587 AN: 10272

Middle Eastern (MID) AF: 0.272 AC: 79 AN: 290

European-Non Finnish (NFE) AF: 0.323 AC: 21747 AN: 67424

Other (OTH) AF: 0.389 AC: 807 AN: 2074

Alfa AF: 0.342 Hom.: 4094

Bravo AF: 0.420

Asia WGS AF: 0.493 AC: 1713 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 63% of patients studied by a panel of primary immunodeficiencies. Number of patients: 60. Only high quality variants are reported. -

not provided Benign:1

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.58
DANN	Benign	0.19
PhyloP100		-4.8
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: rs1122385; hg19: chr19-17942370;