19-17826949-C-T

Variant names:

• chr19-17826949-C-T
• rs3212798
• NM_000215.4:c.3208-39G>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.3208-39G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,594,644 control chromosomes in the GnomAD database, including 30,104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5176 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24928 hom.)
• Consequence: JAK3 NM_000215.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.192
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-17826949-C-T is Benign according to our data. Variant chr19-17826949-C-T is described in ClinVar as Benign. ClinVar VariationId is 1290849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.409 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.3208-39G>A		intron	N/A	NP_000206.2
	JAK3	NM_001440439.1		c.3208-39G>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.3208-39G>A		intron	N/A	ENSP00000391676.1
	JAK3	ENST00000527670.5	TSL:1	c.3208-39G>A		intron	N/A	ENSP00000432511.1
	JAK3	ENST00000526008.6	TSL:2	n.*1765-39G>A		intron	N/A	ENSP00000513006.1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35238 AN: 151960 Hom.: 5153 Cov.: 32

Gnomad AFR AF: 0.414

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.0168

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.212

GnomAD2 exomes AF: 0.165 AC: 38952 AN: 235540 AF XY: 0.162

Gnomad AFR exome AF: 0.422

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.0171

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.179

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.178 AC: 257393 AN: 1442566 Hom.: 24928 Cov.: 31 AF XY: 0.177 AC XY: 126571 AN XY: 716964

African (AFR) AF: 0.420 AC: 13985 AN: 33322

American (AMR) AF: 0.111 AC: 4957 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 5169 AN: 25848

East Asian (EAS) AF: 0.0170 AC: 672 AN: 39530

South Asian (SAS) AF: 0.137 AC: 11741 AN: 85982

European-Finnish (FIN) AF: 0.147 AC: 6119 AN: 41666

Middle Eastern (MID) AF: 0.173 AC: 914 AN: 5292

European-Non Finnish (NFE) AF: 0.183 AC: 202728 AN: 1106520

Other (OTH) AF: 0.185 AC: 11108 AN: 59940

GnomAD4 genome AF: 0.232 AC: 35308 AN: 152078 Hom.: 5176 Cov.: 32 AF XY: 0.226 AC XY: 16770 AN XY: 74336

African (AFR) AF: 0.414 AC: 17163 AN: 41438

American (AMR) AF: 0.156 AC: 2377 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 702 AN: 3470

East Asian (EAS) AF: 0.0168 AC: 87 AN: 5176

South Asian (SAS) AF: 0.138 AC: 666 AN: 4822

European-Finnish (FIN) AF: 0.137 AC: 1452 AN: 10584

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12274 AN: 67996

Other (OTH) AF: 0.210 AC: 445 AN: 2116

Alfa AF: 0.190 Hom.: 2400

Bravo AF: 0.241

Asia WGS AF: 0.104 AC: 360 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	3.2
DANN	Benign	0.57
PhyloP100		-0.19
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: rs3212798; hg19: chr19-17937758; COSMIC: COSV101512982;