rs3212750

Variant names:

• chr19-17838395-G-A
• rs3212750
• NM_000215.4:c.1442-5C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-17838395-G-A
• chr19-17838395-G-C
• chr19-17838395-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000215.4(JAK3):​c.1442-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,614,122 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (13 hom., cov: 31)
  • Exomes 𝑓: 0.00068 (13 hom.)
• Consequence: JAK3 NM_000215.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006506
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.181
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-17838395-G-A is Benign according to our data. Variant chr19-17838395-G-A is described in ClinVar as Benign. ClinVar VariationId is 137596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00694 (1056/152252) while in subpopulation AFR AF = 0.0238 (988/41546). AF 95% confidence interval is 0.0225. There are 13 homozygotes in GnomAd4. There are 530 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.1442-5C>T		splice_region_variant, intron_variant	Intron 10 of 23	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.1442-5C>T		splice_region_variant, intron_variant	Intron 10 of 23		NP_001427368.1
JAK3	XM_011527991.3	c.1442-5C>T		splice_region_variant, intron_variant	Intron 10 of 13		XP_011526293.2
JAK3	XR_007066796.1	n.1492-5C>T		splice_region_variant, intron_variant	Intron 10 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.1442-5C>T		splice_region_variant, intron_variant	Intron 10 of 23	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes AF: 0.00686 AC: 1043 AN: 152134 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

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: 0.0000294

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00160 AC: 403 AN: 251484 AF XY: 0.00113

Gnomad AFR exome AF: 0.0220

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000683 AC: 998 AN: 1461870 Hom.: 13 Cov.: 33 AF XY: 0.000589 AC XY: 428 AN XY: 727236

African (AFR) AF: 0.0251 AC: 841 AN: 33480

American (AMR) AF: 0.00119 AC: 53 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111998

Other (OTH) AF: 0.00149 AC: 90 AN: 60390

GnomAD4 genome AF: 0.00694 AC: 1056 AN: 152252 Hom.: 13 Cov.: 31 AF XY: 0.00712 AC XY: 530 AN XY: 74440

African (AFR) AF: 0.0238 AC: 988 AN: 41546

American (AMR) AF: 0.00360 AC: 55 AN: 15288

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: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00522 AC: 11 AN: 2108

Alfa AF: 0.00440 Hom.: 5

Bravo AF: 0.00784

Asia WGS AF: 0.00404 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 22, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The JAK3 c.1442-5C>T variant involves the alteration of a non-conserved nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 582/277228 control chromosomes (6 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.022258 (535/24036 with 5 homozygotes). This frequency is about 21 times the estimated maximal expected allele frequency of a pathogenic JAK3 variant (0.0010801), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. This variant, to our knowledge, has not been reported via publications in affected individuals. In addition, one clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as benign. -

Apr 29, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

T-B+ severe combined immunodeficiency due to JAK3 deficiency Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

JAK3-related disorder Benign:1

Mar 27, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.2
DANN	Benign	0.56
PhyloP100		0.18
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000065
dbscSNV1_RF	Benign	0.0020
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: rs3212750; hg19: chr19-17949204;