chr19-17840369-G-A

Variant names:

• chr19-17840369-G-A
• rs3212741
• NM_000215.4:c.1143-28C>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.1143-28C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,453,662 control chromosomes in the GnomAD database, including 31,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2359 hom., cov: 30)
  • Exomes 𝑓: 0.20 (28830 hom.)
• Consequence: JAK3 NM_000215.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.43
• 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=-0.82).
• BP6: Variant 19-17840369-G-A is Benign according to our data. Variant chr19-17840369-G-A is described in ClinVar as Benign. ClinVar VariationId is 1221017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000215.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	NM_000215.4	MANE Select	c.1143-28C>T		intron	N/A	NP_000206.2
	JAK3	NM_001440439.1		c.1143-28C>T		intron	N/A	NP_001427368.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	ENST00000458235.7	TSL:5 MANE Select	c.1143-28C>T		intron	N/A	ENSP00000391676.1
	JAK3	ENST00000527670.5	TSL:1	c.1143-28C>T		intron	N/A	ENSP00000432511.1
	JAK3	ENST00000534444.1	TSL:1	c.1143-28C>T		intron	N/A	ENSP00000436421.1

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23642 AN: 151872 Hom.: 2360 Cov.: 30

Gnomad AFR AF: 0.0430

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.0480

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.175

GnomAD2 exomes AF: 0.169 AC: 39859 AN: 236188 AF XY: 0.173

Gnomad AFR exome AF: 0.0392

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.194

Gnomad EAS exome AF: 0.0449

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.225

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.204 AC: 265752 AN: 1301672 Hom.: 28830 Cov.: 19 AF XY: 0.202 AC XY: 132491 AN XY: 654784

African (AFR) AF: 0.0390 AC: 1177 AN: 30144

American (AMR) AF: 0.105 AC: 4559 AN: 43430

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 4722 AN: 25002

East Asian (EAS) AF: 0.0481 AC: 1862 AN: 38676

South Asian (SAS) AF: 0.132 AC: 10846 AN: 82234

European-Finnish (FIN) AF: 0.218 AC: 11418 AN: 52466

Middle Eastern (MID) AF: 0.158 AC: 843 AN: 5342

European-Non Finnish (NFE) AF: 0.227 AC: 219903 AN: 969366

Other (OTH) AF: 0.189 AC: 10422 AN: 55012

GnomAD4 genome AF: 0.156 AC: 23635 AN: 151990 Hom.: 2359 Cov.: 30 AF XY: 0.153 AC XY: 11392 AN XY: 74296

African (AFR) AF: 0.0429 AC: 1780 AN: 41484

American (AMR) AF: 0.140 AC: 2136 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 694 AN: 3468

East Asian (EAS) AF: 0.0476 AC: 245 AN: 5152

South Asian (SAS) AF: 0.125 AC: 602 AN: 4818

European-Finnish (FIN) AF: 0.213 AC: 2253 AN: 10556

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15262 AN: 67956

Other (OTH) AF: 0.173 AC: 365 AN: 2108

Alfa AF: 0.196 Hom.: 3152

Bravo AF: 0.145

Asia WGS AF: 0.0980 AC: 340 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.2
DANN	Benign	0.70
PhyloP100		1.4
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: rs3212741; hg19: chr19-17951178; COSMIC: COSV71685724;