19-17844194-C-T

Variant names:

• chr19-17844194-C-T
• rs3212712
• NM_000215.4:c.184+40G>A

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.184+40G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,539,842 control chromosomes in the GnomAD database, including 85,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (15594 hom., cov: 32)
  • Exomes 𝑓: 0.31 (69850 hom.)
• Consequence: JAK3 NM_000215.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.74
• Publications: 4 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-17844194-C-T is Benign according to our data. Variant chr19-17844194-C-T is described in ClinVar as Benign. ClinVar VariationId is 1291546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000215.4. 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.184+40G>A		intron	N/A	NP_000206.2
	JAK3	NM_001440439.1		c.184+40G>A		intron	N/A	NP_001427368.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	ENST00000458235.7	TSL:5 MANE Select	c.184+40G>A		intron	N/A	ENSP00000391676.1	P52333-1
	JAK3	ENST00000527670.5	TSL:1	c.184+40G>A		intron	N/A	ENSP00000432511.1	P52333-1
	JAK3	ENST00000534444.1	TSL:1	c.184+40G>A		intron	N/A	ENSP00000436421.1	P52333-2

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63238 AN: 151832 Hom.: 15562 Cov.: 32

Gnomad AFR AF: 0.699

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.420

GnomAD2 exomes AF: 0.333 AC: 54007 AN: 162192 AF XY: 0.327

Gnomad AFR exome AF: 0.702

Gnomad AMR exome AF: 0.348

Gnomad ASJ exome AF: 0.359

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.331

GnomAD4 exome AF: 0.309 AC: 429415 AN: 1387892 Hom.: 69850 Cov.: 28 AF XY: 0.309 AC XY: 211770 AN XY: 686182

African (AFR) AF: 0.711 AC: 22459 AN: 31578

American (AMR) AF: 0.358 AC: 12987 AN: 36258

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 8688 AN: 25120

East Asian (EAS) AF: 0.338 AC: 12250 AN: 36264

South Asian (SAS) AF: 0.331 AC: 26271 AN: 79380

European-Finnish (FIN) AF: 0.228 AC: 10884 AN: 47748

Middle Eastern (MID) AF: 0.334 AC: 1361 AN: 4070

European-Non Finnish (NFE) AF: 0.294 AC: 314875 AN: 1069864

Other (OTH) AF: 0.341 AC: 19640 AN: 57610

GnomAD4 genome AF: 0.417 AC: 63319 AN: 151950 Hom.: 15594 Cov.: 32 AF XY: 0.412 AC XY: 30622 AN XY: 74288

African (AFR) AF: 0.699 AC: 28954 AN: 41422

American (AMR) AF: 0.399 AC: 6093 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1203 AN: 3468

East Asian (EAS) AF: 0.336 AC: 1731 AN: 5152

South Asian (SAS) AF: 0.327 AC: 1580 AN: 4828

European-Finnish (FIN) AF: 0.220 AC: 2322 AN: 10570

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.296 AC: 20093 AN: 67938

Other (OTH) AF: 0.420 AC: 888 AN: 2112

Alfa AF: 0.353 Hom.: 3484

Bravo AF: 0.442

Asia WGS AF: 0.371 AC: 1290 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	-0.89
CADD	Benign	2.4
DANN	Benign	0.63
PhyloP100		-1.7
PromoterAI		0.0020	Neutral
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: rs3212712; hg19: chr19-17955003; COSMIC: COSV101512871;