19-17825450-G-A

Variant names:

• chr19-17825450-G-A
• rs73014967
• NM_000215.4:c.*1293C>T

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.*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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.119
• Publications: 5 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=-0.87).
• 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.*1293C>T		3_prime_UTR_variant	Exon 24 of 24	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.*1293C>T		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.*1293C>T		3_prime_UTR_variant	Exon 24 of 24	5	NM_000215.4	ENSP00000391676.1
JAK3	ENST00000696967.1	n.3845C>T		non_coding_transcript_exon_variant	Exon 19 of 19
JAK3	ENST00000696968.1	n.1901C>T		non_coding_transcript_exon_variant	Exon 3 of 3
JAK3	ENST00000527031.5	n.2279-140C>T		intron_variant	Intron 13 of 13	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

African (AFR) AF: 0.125 AC: 357 AN: 2862

American (AMR) AF: 0.152 AC: 280 AN: 1848

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 774 AN: 3996

East Asian (EAS) AF: 0.125 AC: 1182 AN: 9468

South Asian (SAS) AF: 0.220 AC: 125 AN: 568

European-Finnish (FIN) AF: 0.140 AC: 7 AN: 50

Middle Eastern (MID) AF: 0.324 AC: 127 AN: 392

European-Non Finnish (NFE) AF: 0.219 AC: 8564 AN: 39038

Other (OTH) AF: 0.203 AC: 1094 AN: 5388

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

African (AFR) AF: 0.127 AC: 5258 AN: 41460

American (AMR) AF: 0.157 AC: 2393 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 750 AN: 3468

East Asian (EAS) AF: 0.132 AC: 683 AN: 5172

South Asian (SAS) AF: 0.225 AC: 1084 AN: 4824

European-Finnish (FIN) AF: 0.112 AC: 1189 AN: 10586

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14812 AN: 67954

Other (OTH) AF: 0.184 AC: 386 AN: 2102

Alfa AF: 0.186 Hom.: 1462

Bravo AF: 0.174

Asia WGS AF: 0.165 AC: 574 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 13, 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	-0.87
CADD	Benign	2.9
DANN	Benign	0.76
PhyloP100		0.12
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: rs73014967; hg19: chr19-17936259;