rs3212780

Variant names:

• chr19-17830033-G-A
• rs3212780
• ENST00000534444.1:c.3282C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000534444.1(JAK3):​c.3282C>T​(p.Ala1094Ala) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A1094A) has been classified as Uncertain significance.

• 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:3
• Conservation: PhyloP100: -2.69
• Publications: 11 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 -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 VariationId is 1283176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000534444.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	NM_000215.4	MANE Select	c.3207+75C>T		intron	N/A	NP_000206.2
	JAK3	NM_001440439.1		c.3207+75C>T		intron	N/A	NP_001427368.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	ENST00000534444.1	TSL:1	c.3282C>T	p.Ala1094Ala	synonymous	Exon 23 of 23	ENSP00000436421.1
	JAK3	ENST00000458235.7	TSL:5 MANE Select	c.3207+75C>T		intron	N/A	ENSP00000391676.1
	JAK3	ENST00000527670.5	TSL:1	c.3207+75C>T		intron	N/A	ENSP00000432511.1

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

GnomAD2 exomes AF: 0.212 AC: 29325 AN: 138050 AF XY: 0.216

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 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

African (AFR) AF: 0.0722 AC: 1599 AN: 22160

American (AMR) AF: 0.158 AC: 5555 AN: 35130

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 5703 AN: 22204

East Asian (EAS) AF: 0.0234 AC: 784 AN: 33540

South Asian (SAS) AF: 0.195 AC: 13530 AN: 69480

European-Finnish (FIN) AF: 0.299 AC: 12136 AN: 40634

Middle Eastern (MID) AF: 0.206 AC: 981 AN: 4752

European-Non Finnish (NFE) AF: 0.277 AC: 175974 AN: 634610

Other (OTH) AF: 0.227 AC: 9467 AN: 41758

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

African (AFR) AF: 0.0771 AC: 3204 AN: 41544

American (AMR) AF: 0.208 AC: 3187 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 877 AN: 3470

East Asian (EAS) AF: 0.0272 AC: 141 AN: 5186

South Asian (SAS) AF: 0.181 AC: 873 AN: 4830

European-Finnish (FIN) AF: 0.309 AC: 3269 AN: 10580

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.277 AC: 18799 AN: 67976

Other (OTH) AF: 0.214 AC: 452 AN: 2114

Alfa AF: 0.220 Hom.: 1483

Bravo AF: 0.192

Asia WGS AF: 0.0990 AC: 345 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.7
DANN	Benign	0.77
PhyloP100		-2.7
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: rs3212780; hg19: chr19-17940842;