rs3212741

chr19-17840369-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000215.4(JAK3):c.1143-28C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,453,662 control chromosomes in the GnomAD database, including 31,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2359 hom., cov: 30)
  • Exomes 𝑓: 0.20 (28830 hom.)
• Consequence: JAK3 NM_000215.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.43

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-17840369-G-A is Benign according to our data. Variant chr19-17840369-G-A is described in ClinVar as [Benign]. Clinvar id is 1221017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK3	NM_000215.4	c.1143-28C>T		intron_variant		ENST00000458235.7
JAK3	XM_011527991.3	c.1143-28C>T		intron_variant
JAK3	XM_047438786.1	c.1143-28C>T		intron_variant
JAK3	XR_007066796.1	n.1193-28C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK3	ENST00000458235.7	c.1143-28C>T		intron_variant		5	NM_000215.4	P1

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23642 AN: 151872 Hom.: 2360 Cov.: 30

Gnomad AFR AF: 0.0430

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.0480

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.175

GnomAD3 exomes AF: 0.169 AC: 39859 AN: 236188 Hom.: 3822 AF XY: 0.173 AC XY: 22077 AN XY: 127976

Gnomad AFR exome AF: 0.0392

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.194

Gnomad EAS exome AF: 0.0449

Gnomad SAS exome AF: 0.133

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.225

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.204 AC: 265752 AN: 1301672 Hom.: 28830 Cov.: 19 AF XY: 0.202 AC XY: 132491 AN XY: 654784

Gnomad4 AFR exome AF: 0.0390

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.189

Gnomad4 EAS exome AF: 0.0481

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.218

Gnomad4 NFE exome AF: 0.227

Gnomad4 OTH exome AF: 0.189

GnomAD4 genome AF: 0.156 AC: 23635 AN: 151990 Hom.: 2359 Cov.: 30 AF XY: 0.153 AC XY: 11392 AN XY: 74296

Gnomad4 AFR AF: 0.0429

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.200

Gnomad4 EAS AF: 0.0476

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.213

Gnomad4 NFE AF: 0.225

Gnomad4 OTH AF: 0.173

Alfa AF: 0.199 Hom.: 1624

Bravo AF: 0.145

Asia WGS AF: 0.0980 AC: 340 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	3.2
Dann	Benign	0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs3212741; hg19: chr19-17951178; COSMIC: COSV71685724; COSMIC: COSV71685724;