rs3213408

Variant names:

• chr19-17838052-C-T
• rs3213408
• NM_000215.4:c.1581G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The ENST00000458235.7(JAK3):​c.1581G>A​(p.Leu527Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,614,114 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (6 hom.)
• Consequence: JAK3 ENST00000458235.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.0370
• Publications: 1 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 19-17838052-C-T is Benign according to our data. Variant chr19-17838052-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 464097.
• BP7: Synonymous conserved (PhyloP=-0.037 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000458235.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	NM_000215.4	MANE Select	c.1581G>A	p.Leu527Leu	synonymous	Exon 12 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.1581G>A	p.Leu527Leu	synonymous	Exon 12 of 24	NP_001427368.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	ENST00000458235.7	TSL:5 MANE Select	c.1581G>A	p.Leu527Leu	synonymous	Exon 12 of 24	ENSP00000391676.1
	JAK3	ENST00000527670.5	TSL:1	c.1581G>A	p.Leu527Leu	synonymous	Exon 11 of 23	ENSP00000432511.1
	JAK3	ENST00000534444.1	TSL:1	c.1581G>A	p.Leu527Leu	synonymous	Exon 12 of 23	ENSP00000436421.1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00123 AC: 310 AN: 251478 AF XY: 0.00116

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00224

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00209 AC: 3052 AN: 1461884 Hom.: 6 Cov.: 33 AF XY: 0.00202 AC XY: 1467 AN XY: 727242

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000268 AC: 12 AN: 44724

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

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

South Asian (SAS) AF: 0.00114 AC: 98 AN: 86252

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00258 AC: 2864 AN: 1112010

Other (OTH) AF: 0.00104 AC: 63 AN: 60396

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74430

African (AFR) AF: 0.000482 AC: 20 AN: 41536

American (AMR) AF: 0.000327 AC: 5 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4814

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00222 AC: 151 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00116

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00124

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	T-B+ severe combined immunodeficiency due to JAK3 deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	7.1
DANN	Benign	0.71
PhyloP100		-0.037
Mutation Taster		=98/2	polymorphism

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: rs3213408; hg19: chr19-17948861;