rs3213415

chr19-17825546-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000215.4(JAK3):c.*1197G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 199,536 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0073 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0081 (1 hom.)
• Consequence: JAK3 NM_000215.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.400

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=-0.84).
• BP6: Variant 19-17825546-C-T is Benign according to our data. Variant chr19-17825546-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 328474.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00734 (1118/152262) while in subpopulation AMR AF= 0.0111 (170/15278). AF 95% confidence interval is 0.0103. There are 8 homozygotes in gnomad4. There are 530 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK3	NM_000215.4	c.*1197G>A		3_prime_UTR_variant	24/24	ENST00000458235.7
JAK3	XM_047438786.1	c.*1197G>A		3_prime_UTR_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK3	ENST00000458235.7	c.*1197G>A		3_prime_UTR_variant	24/24	5	NM_000215.4	P1
JAK3	ENST00000696967.1	n.3749G>A		non_coding_transcript_exon_variant	19/19
JAK3	ENST00000696968.1	n.1805G>A		non_coding_transcript_exon_variant	3/3
JAK3	ENST00000527031.5	n.2279-236G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00735 AC: 1118 AN: 152144 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00766

GnomAD4 exome AF: 0.00812 AC: 384 AN: 47274 Hom.: 1 Cov.: 0 AF XY: 0.00876 AC XY: 192 AN XY: 21918

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00317

Gnomad4 ASJ exome AF: 0.00709

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00503

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0107

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.00734 AC: 1118 AN: 152262 Hom.: 8 Cov.: 31 AF XY: 0.00712 AC XY: 530 AN XY: 74456

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.0111

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00821 Hom.: 0

Bravo AF: 0.00739

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	2.6
Dann	Benign	0.84

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: rs3213415; hg19: chr19-17936355;