rs7254346

Variant names:

• chr19-17847968-T-C
• rs7254346
• NM_000215.4:c.-36A>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.-36A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,036,266 control chromosomes in the GnomAD database, including 13,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (7265 hom., cov: 33)
  • Exomes 𝑓: 0.091 (6226 hom.)
• Consequence: JAK3 NM_000215.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.861
• Publications: 17 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=-0.86).
• BP6: Variant 19-17847968-T-C is Benign according to our data. Variant chr19-17847968-T-C is described in ClinVar as Benign. ClinVar VariationId is 328525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.-36A>G		5_prime_UTR_variant	Exon 1 of 24	ENST00000458235.7	NP_000206.2
JAK3	XR_007066796.1	n.15A>G		non_coding_transcript_exon_variant	Exon 1 of 20
JAK3	NM_001440439.1	c.-67A>G		5_prime_UTR_variant	Exon 1 of 24		NP_001427368.1
JAK3	XM_011527991.3	c.-36A>G		5_prime_UTR_variant	Exon 1 of 14		XP_011526293.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.-36A>G		5_prime_UTR_variant	Exon 1 of 24	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33472 AN: 152060 Hom.: 7242 Cov.: 33

Gnomad AFR AF: 0.561

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0746

Gnomad OTH AF: 0.193

GnomAD4 exome AF: 0.0911 AC: 80578 AN: 884088 Hom.: 6226 Cov.: 29 AF XY: 0.0900 AC XY: 36732 AN XY: 408346

African (AFR) AF: 0.588 AC: 10447 AN: 17758

American (AMR) AF: 0.120 AC: 283 AN: 2352

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 866 AN: 8322

East Asian (EAS) AF: 0.212 AC: 2479 AN: 11688

South Asian (SAS) AF: 0.113 AC: 1919 AN: 16958

European-Finnish (FIN) AF: 0.0472 AC: 15 AN: 318

Middle Eastern (MID) AF: 0.0919 AC: 318 AN: 3462

European-Non Finnish (NFE) AF: 0.0763 AC: 60391 AN: 791666

Other (OTH) AF: 0.122 AC: 3860 AN: 31564

GnomAD4 genome AF: 0.220 AC: 33553 AN: 152178 Hom.: 7265 Cov.: 33 AF XY: 0.217 AC XY: 16178 AN XY: 74400

African (AFR) AF: 0.561 AC: 23298 AN: 41502

American (AMR) AF: 0.149 AC: 2281 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 359 AN: 3472

East Asian (EAS) AF: 0.222 AC: 1146 AN: 5168

South Asian (SAS) AF: 0.117 AC: 565 AN: 4830

European-Finnish (FIN) AF: 0.0325 AC: 345 AN: 10612

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0746 AC: 5071 AN: 68000

Other (OTH) AF: 0.196 AC: 415 AN: 2112

Alfa AF: 0.108 Hom.: 3232

Bravo AF: 0.243

Asia WGS AF: 0.206 AC: 715 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

T-B+ severe combined immunodeficiency due to JAK3 deficiency Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.0
DANN	Benign	0.35
PhyloP100		-0.86
PromoterAI		-0.17	Neutral
Mutation Taster		=300/0	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: rs7254346; hg19: chr19-17958777;