chr19-17824910-C-T

Variant names:

• chr19-17824910-C-T
• rs546293977
• NM_000215.4:c.*1833G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000215.4(JAK3):​c.*1833G>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 0.00135 in 218,498 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: JAK3 NM_000215.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.187
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.*1833G>A		3_prime_UTR_variant	Exon 24 of 24	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.*1833G>A		3_prime_UTR_variant	Exon 24 of 24		NP_001427368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.*1833G>A		3_prime_UTR_variant	Exon 24 of 24	5	NM_000215.4	ENSP00000391676.1
JAK3	ENST00000527031.5	n.2679G>A		non_coding_transcript_exon_variant	Exon 14 of 14	2
JAK3	ENST00000696967.1	n.4385G>A		non_coding_transcript_exon_variant	Exon 19 of 19
JAK3	ENST00000696968.1	n.*37G>A		downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.00187 AC: 124 AN: 66192 Hom.: 2 Cov.: 0 AF XY: 0.00182 AC XY: 56 AN XY: 30816

African (AFR) AF: 0.000334 AC: 1 AN: 2996

American (AMR) AF: 0.00304 AC: 6 AN: 1972

Ashkenazi Jewish (ASJ) AF: 0.00925 AC: 39 AN: 4218

East Asian (EAS) AF: 0.00 AC: 0 AN: 9692

South Asian (SAS) AF: 0.00 AC: 0 AN: 572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 60

Middle Eastern (MID) AF: 0.00246 AC: 1 AN: 406

European-Non Finnish (NFE) AF: 0.00162 AC: 66 AN: 40696

Other (OTH) AF: 0.00197 AC: 11 AN: 5580

GnomAD4 genome AF: 0.00113 AC: 172 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000967 AC XY: 72 AN XY: 74472

African (AFR) AF: 0.000337 AC: 14 AN: 41574

American (AMR) AF: 0.000981 AC: 15 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 68032

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00137

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.4
DANN	Benign	0.51
PhyloP100		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs546293977; hg19: chr19-17935719;