19-17825450-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000215.4(JAK3):c.*1293C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 215,624 control chromosomes in the GnomAD database, including 3,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (2557 hom., cov: 31)
  • Exomes 𝑓: 0.20 (1301 hom.)
• Consequence: JAK3 NM_000215.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.119

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-17825450-G-A is Benign according to our data. Variant chr19-17825450-G-A is described in ClinVar as [Benign]. Clinvar id is 328471.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK3	NM_000215.4	c.*1293C>T		3_prime_UTR_variant	24/24	ENST00000458235.7
JAK3	XM_047438786.1	c.*1293C>T		3_prime_UTR_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK3	ENST00000458235.7	c.*1293C>T		3_prime_UTR_variant	24/24	5	NM_000215.4	P1
JAK3	ENST00000696967.1	n.3845C>T		non_coding_transcript_exon_variant	19/19
JAK3	ENST00000696968.1	n.1901C>T		non_coding_transcript_exon_variant	3/3
JAK3	ENST00000527031.5	n.2279-140C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26783 AN: 151900 Hom.: 2557 Cov.: 31

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.186

GnomAD4 exome AF: 0.197 AC: 12510 AN: 63610 Hom.: 1301 Cov.: 0 AF XY: 0.197 AC XY: 5834 AN XY: 29550

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.152

Gnomad4 ASJ exome AF: 0.194

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.220

Gnomad4 FIN exome AF: 0.140

Gnomad4 NFE exome AF: 0.219

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.176 AC: 26802 AN: 152014 Hom.: 2557 Cov.: 31 AF XY: 0.172 AC XY: 12767 AN XY: 74302

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.216

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.184

Alfa AF: 0.199 Hom.: 862

Bravo AF: 0.174

Asia WGS AF: 0.165 AC: 574 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	2.9
Dann	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs73014967; hg19: chr19-17936259;