19-17825195-G-A

Variant names:

• chr19-17825195-G-A
• rs191522931
• NM_000215.4:c.*1548C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000215.4(JAK3):​c.*1548C>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 0.000253 in 229,646 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: JAK3 NM_000215.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.640
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-17825195-G-A is Benign according to our data. Variant chr19-17825195-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 328466.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000243 (37/152252) while in subpopulation EAS AF = 0.00617 (32/5186). AF 95% confidence interval is 0.00449. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.*1548C>T		3_prime_UTR_variant	Exon 24 of 24	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.*1548C>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.*1548C>T		3_prime_UTR_variant	Exon 24 of 24	5	NM_000215.4	ENSP00000391676.1
JAK3	ENST00000527031.5	n.2394C>T		non_coding_transcript_exon_variant	Exon 14 of 14	2
JAK3	ENST00000696967.1	n.4100C>T		non_coding_transcript_exon_variant	Exon 19 of 19
JAK3	ENST00000696968.1	n.2156C>T		non_coding_transcript_exon_variant	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00616

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.000271 AC: 21 AN: 77394 Hom.: 1 Cov.: 0 AF XY: 0.000309 AC XY: 11 AN XY: 35648

African (AFR) AF: 0.000542 AC: 2 AN: 3688

American (AMR) AF: 0.00 AC: 0 AN: 2388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4916

East Asian (EAS) AF: 0.000914 AC: 10 AN: 10940

South Asian (SAS) AF: 0.00 AC: 0 AN: 672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 66

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 476

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 47768

Other (OTH) AF: 0.00139 AC: 9 AN: 6480

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74434

African (AFR) AF: 0.00 AC: 0 AN: 41534

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00617 AC: 32 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000423

Asia WGS AF: 0.00231 AC: 8 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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 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	-0.87
CADD	Benign	0.95
DANN	Benign	0.49
PhyloP100		-0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs191522931; hg19: chr19-17936004;