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, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.*1926A>G		3_prime_UTR_variant	Exon 24 of 24	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.*1926A>G		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.*1926A>G		3_prime_UTR_variant	Exon 24 of 24	5	NM_000215.4	ENSP00000391676.1
JAK3	ENST00000527031.5	n.2772A>G		non_coding_transcript_exon_variant	Exon 14 of 14	2
JAK3	ENST00000696967.1	n.4478A>G		non_coding_transcript_exon_variant	Exon 19 of 19
JAK3	ENST00000696968.1	n.*130A>G		downstream_gene_variant

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

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;