chr19-17825546-C-T

Variant names:

• chr19-17825546-C-T
• rs3213415
• NM_000215.4:c.*1197G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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 -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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.*1197G>A		3_prime_UTR_variant	Exon 24 of 24	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.*1197G>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.*1197G>A		3_prime_UTR_variant	Exon 24 of 24	5	NM_000215.4	ENSP00000391676.1
JAK3	ENST00000696967.1	n.3749G>A		non_coding_transcript_exon_variant	Exon 19 of 19
JAK3	ENST00000696968.1	n.1805G>A		non_coding_transcript_exon_variant	Exon 3 of 3
JAK3	ENST00000527031.5	n.2279-236G>A		intron_variant	Intron 13 of 13	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

African (AFR) AF: 0.00158 AC: 3 AN: 1896

American (AMR) AF: 0.00317 AC: 4 AN: 1262

Ashkenazi Jewish (ASJ) AF: 0.00709 AC: 21 AN: 2962

East Asian (EAS) AF: 0.00 AC: 0 AN: 7860

South Asian (SAS) AF: 0.00503 AC: 2 AN: 398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28

Middle Eastern (MID) AF: 0.0211 AC: 6 AN: 284

European-Non Finnish (NFE) AF: 0.0107 AC: 307 AN: 28622

Other (OTH) AF: 0.0103 AC: 41 AN: 3962

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

African (AFR) AF: 0.00207 AC: 86 AN: 41556

American (AMR) AF: 0.0111 AC: 170 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4828

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10608

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0110 AC: 748 AN: 68022

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

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

Jan 12, 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	-0.84
CADD	Benign	2.6
DANN	Benign	0.84
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism

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: rs3213415; hg19: chr19-17936355;