19-17837923-T-C

Variant names:

• chr19-17837923-T-C
• rs3212752
• NM_000215.4:c.1701+9A>G

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.1701+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0763 in 1,613,714 control chromosomes in the GnomAD database, including 6,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1473 hom., cov: 31)
  • Exomes 𝑓: 0.072 (4644 hom.)
• Consequence: JAK3 NM_000215.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.218
• Publications: 19 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-17837923-T-C is Benign according to our data. Variant chr19-17837923-T-C is described in ClinVar as Benign. ClinVar VariationId is 137597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 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.1701+9A>G		intron	N/A	NP_000206.2
	JAK3	NM_001440439.1		c.1701+9A>G		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.1701+9A>G		intron	N/A	ENSP00000391676.1	P52333-1
	JAK3	ENST00000527670.5	TSL:1	c.1701+9A>G		intron	N/A	ENSP00000432511.1	P52333-1
	JAK3	ENST00000534444.1	TSL:1	c.1701+9A>G		intron	N/A	ENSP00000436421.1	P52333-2

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17917 AN: 151894 Hom.: 1466 Cov.: 31

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0892

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.0577

Gnomad SAS AF: 0.0720

Gnomad FIN AF: 0.0970

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0718

Gnomad OTH AF: 0.106

GnomAD2 exomes AF: 0.0794 AC: 19980 AN: 251490 AF XY: 0.0770

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.0557

Gnomad ASJ exome AF: 0.0419

Gnomad EAS exome AF: 0.0564

Gnomad FIN exome AF: 0.0949

Gnomad NFE exome AF: 0.0716

Gnomad OTH exome AF: 0.0723

GnomAD4 exome AF: 0.0719 AC: 105131 AN: 1461702 Hom.: 4644 Cov.: 33 AF XY: 0.0714 AC XY: 51885 AN XY: 727158

African (AFR) AF: 0.244 AC: 8175 AN: 33476

American (AMR) AF: 0.0571 AC: 2553 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0401 AC: 1048 AN: 26130

East Asian (EAS) AF: 0.0481 AC: 1911 AN: 39694

South Asian (SAS) AF: 0.0740 AC: 6382 AN: 86256

European-Finnish (FIN) AF: 0.0958 AC: 5113 AN: 53382

Middle Eastern (MID) AF: 0.0662 AC: 382 AN: 5768

European-Non Finnish (NFE) AF: 0.0674 AC: 74909 AN: 1111896

Other (OTH) AF: 0.0771 AC: 4658 AN: 60382

GnomAD4 genome AF: 0.118 AC: 17962 AN: 152012 Hom.: 1473 Cov.: 31 AF XY: 0.118 AC XY: 8741 AN XY: 74320

African (AFR) AF: 0.233 AC: 9629 AN: 41404

American (AMR) AF: 0.0891 AC: 1359 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 126 AN: 3468

East Asian (EAS) AF: 0.0573 AC: 296 AN: 5166

South Asian (SAS) AF: 0.0716 AC: 346 AN: 4830

European-Finnish (FIN) AF: 0.0970 AC: 1027 AN: 10584

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0718 AC: 4884 AN: 67988

Other (OTH) AF: 0.110 AC: 232 AN: 2110

Alfa AF: 0.0837 Hom.: 1552

Bravo AF: 0.119

Asia WGS AF: 0.108 AC: 375 AN: 3478

EpiCase AF: 0.0636

EpiControl AF: 0.0635

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.6
DANN	Benign	0.46
PhyloP100		0.22
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: rs3212752; hg19: chr19-17948732; COSMIC: COSV71685554; COSMIC: COSV71685554;