19-17824817-T-C

Variant names:

• chr19-17824817-T-C
• rs11888
• NM_000215.4:c.*1926A>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.*1926A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 196,984 control chromosomes in the GnomAD database, including 14,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11226 hom., cov: 32)
  • Exomes 𝑓: 0.38 (3352 hom.)
• Consequence: JAK3 NM_000215.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.211
• Publications: 18 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=-0.86).
• BP6: Variant 19-17824817-T-C is Benign according to our data. Variant chr19-17824817-T-C is described in ClinVar as Benign. ClinVar VariationId is 328462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.429 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.*1926A>G		3_prime_UTR	Exon 24 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.*1926A>G		3_prime_UTR	Exon 24 of 24	NP_001427368.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	ENST00000458235.7	TSL:5 MANE Select	c.*1926A>G		3_prime_UTR	Exon 24 of 24	ENSP00000391676.1	P52333-1
	JAK3	ENST00000527031.5	TSL:2	n.2772A>G		non_coding_transcript_exon	Exon 14 of 14
	JAK3	ENST00000696967.1		n.4478A>G		non_coding_transcript_exon	Exon 19 of 19

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57932 AN: 151924 Hom.: 11212 Cov.: 32

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.364

GnomAD4 exome AF: 0.378 AC: 16988 AN: 44942 Hom.: 3352 Cov.: 0 AF XY: 0.374 AC XY: 7857 AN XY: 21004

African (AFR) AF: 0.448 AC: 835 AN: 1864

American (AMR) AF: 0.359 AC: 430 AN: 1198

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 739 AN: 2888

East Asian (EAS) AF: 0.468 AC: 3495 AN: 7472

South Asian (SAS) AF: 0.387 AC: 157 AN: 406

European-Finnish (FIN) AF: 0.385 AC: 10 AN: 26

Middle Eastern (MID) AF: 0.387 AC: 103 AN: 266

European-Non Finnish (NFE) AF: 0.363 AC: 9853 AN: 27122

Other (OTH) AF: 0.369 AC: 1366 AN: 3700

GnomAD4 genome AF: 0.381 AC: 57984 AN: 152042 Hom.: 11226 Cov.: 32 AF XY: 0.381 AC XY: 28306 AN XY: 74336

African (AFR) AF: 0.434 AC: 18016 AN: 41466

American (AMR) AF: 0.372 AC: 5679 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 874 AN: 3472

East Asian (EAS) AF: 0.429 AC: 2215 AN: 5162

South Asian (SAS) AF: 0.405 AC: 1954 AN: 4820

European-Finnish (FIN) AF: 0.316 AC: 3340 AN: 10574

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.364 AC: 24713 AN: 67958

Other (OTH) AF: 0.362 AC: 764 AN: 2108

Alfa AF: 0.381 Hom.: 5291

Bravo AF: 0.384

Asia WGS AF: 0.379 AC: 1316 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.88
PhyloP100		-0.21
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: rs11888; hg19: chr19-17935626;