rs3212780

Positions:

• chr19-17830033-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000534444.1(JAK3):​c.3282C>T​(p.Ala1094=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,056,466 control chromosomes in the GnomAD database, including 34,324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3927 hom., cov: 32)
  • Exomes 𝑓: 0.25 (30397 hom.)
• Consequence: JAK3 ENST00000534444.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.69

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-17830033-G-A is Benign according to our data. Variant chr19-17830033-G-A is described in ClinVar as [Benign]. Clinvar id is 1283176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-17830033-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.68 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK3	NM_000215.4	c.3207+75C>T		intron_variant		ENST00000458235.7
JAK3	XM_047438786.1	c.3207+75C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK3	ENST00000458235.7	c.3207+75C>T		intron_variant		5	NM_000215.4	P1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31159 AN: 152080 Hom.: 3929 Cov.: 32

Gnomad AFR AF: 0.0774

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.0271

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.217

GnomAD3 exomes AF: 0.212 AC: 29325 AN: 138050 Hom.: 3672 AF XY: 0.216 AC XY: 16257 AN XY: 75296

Gnomad AFR exome AF: 0.0722

Gnomad AMR exome AF: 0.151

Gnomad ASJ exome AF: 0.258

Gnomad EAS exome AF: 0.0237

Gnomad SAS exome AF: 0.192

Gnomad FIN exome AF: 0.310

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.250 AC: 225729 AN: 904268 Hom.: 30397 Cov.: 12 AF XY: 0.248 AC XY: 115322 AN XY: 464788

Gnomad4 AFR exome AF: 0.0722

Gnomad4 AMR exome AF: 0.158

Gnomad4 ASJ exome AF: 0.257

Gnomad4 EAS exome AF: 0.0234

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.299

Gnomad4 NFE exome AF: 0.277

Gnomad4 OTH exome AF: 0.227

GnomAD4 genome AF: 0.205 AC: 31157 AN: 152198 Hom.: 3927 Cov.: 32 AF XY: 0.207 AC XY: 15381 AN XY: 74408

Gnomad4 AFR AF: 0.0771

Gnomad4 AMR AF: 0.208

Gnomad4 ASJ AF: 0.253

Gnomad4 EAS AF: 0.0272

Gnomad4 SAS AF: 0.181

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.277

Gnomad4 OTH AF: 0.214

Alfa AF: 0.222 Hom.: 829

Bravo AF: 0.192

Asia WGS AF: 0.0990 AC: 345 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 28% of patients studied by a panel of primary immunodeficiencies. Number of patients: 25. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.7
DANN	Benign	0.77

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: rs3212780; hg19: chr19-17940842; COSMIC: COSV71685558;