rs55802448

chr19-17841400-G-Achr19-17841400-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000215.4(JAK3):c.1131C>T(p.His377=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,550,872 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (29 hom.)
• Consequence: JAK3 NM_000215.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.86

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 19-17841400-G-A is Benign according to our data. Variant chr19-17841400-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 385188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.86 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00153 (233/152276) while in subpopulation SAS AF= 0.0174 (84/4830). AF 95% confidence interval is 0.0144. There are 4 homozygotes in gnomad4. There are 139 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK3	NM_000215.4	c.1131C>T	p.His377=	synonymous_variant	8/24	ENST00000458235.7
JAK3	XM_047438786.1	c.1131C>T	p.His377=	synonymous_variant	8/24
JAK3	XM_011527991.3	c.1131C>T	p.His377=	synonymous_variant	8/14
JAK3	XR_007066796.1	n.1181C>T		non_coding_transcript_exon_variant	8/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK3	ENST00000458235.7	c.1131C>T	p.His377=	synonymous_variant	8/24	5	NM_000215.4	P1

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 152158 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00305 AC: 476 AN: 155910 Hom.: 7 AF XY: 0.00407 AC XY: 337 AN XY: 82862

Gnomad AFR exome AF: 0.000222

Gnomad AMR exome AF: 0.000200

Gnomad ASJ exome AF: 0.00399

Gnomad EAS exome AF: 0.0000868

Gnomad SAS exome AF: 0.0152

Gnomad FIN exome AF: 0.000152

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.00201 AC: 2815 AN: 1398596 Hom.: 29 Cov.: 35 AF XY: 0.00244 AC XY: 1686 AN XY: 690282

Gnomad4 AFR exome AF: 0.0000942

Gnomad4 AMR exome AF: 0.000334

Gnomad4 ASJ exome AF: 0.00397

Gnomad4 EAS exome AF: 0.0000277

Gnomad4 SAS exome AF: 0.0155

Gnomad4 FIN exome AF: 0.000218

Gnomad4 NFE exome AF: 0.00121

Gnomad4 OTH exome AF: 0.00239

GnomAD4 genome AF: 0.00153 AC: 233 AN: 152276 Hom.: 4 Cov.: 31 AF XY: 0.00187 AC XY: 139 AN XY: 74442

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0174

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00182 Hom.: 0

Bravo AF: 0.00121

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

T-B+ severe combined immunodeficiency due to JAK3 deficiency Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 30, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	2.6
Dann	Benign	0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs55802448; hg19: chr19-17952209; COSMIC: COSV71686029; COSMIC: COSV71686029;