rs3212714

Variant names:

• chr19-17844138-G-A
• rs3212714
• NM_000215.4:c.184+96C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-17844138-G-A
• chr19-17844138-G-C

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.184+96C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 1,359,440 control chromosomes in the GnomAD database, including 65,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9527 hom., cov: 32)
  • Exomes 𝑓: 0.30 (56067 hom.)
• Consequence: JAK3 NM_000215.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.16
• Publications: 7 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=-0.91).
• BP6: Variant 19-17844138-G-A is Benign according to our data. Variant chr19-17844138-G-A is described in ClinVar as Benign. ClinVar VariationId is 1272699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.184+96C>T		intron_variant	Intron 2 of 23	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.184+96C>T		intron_variant	Intron 2 of 23		NP_001427368.1
JAK3	XM_011527991.3	c.184+96C>T		intron_variant	Intron 2 of 13		XP_011526293.2
JAK3	XR_007066796.1	n.234+96C>T		intron_variant	Intron 2 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.184+96C>T		intron_variant	Intron 2 of 23	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52593 AN: 151876 Hom.: 9512 Cov.: 32

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.367

GnomAD4 exome AF: 0.302 AC: 364754 AN: 1207446 Hom.: 56067 AF XY: 0.302 AC XY: 182034 AN XY: 603298

African (AFR) AF: 0.457 AC: 12751 AN: 27904

American (AMR) AF: 0.343 AC: 12130 AN: 35356

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 8206 AN: 23994

East Asian (EAS) AF: 0.347 AC: 12062 AN: 34782

South Asian (SAS) AF: 0.309 AC: 23247 AN: 75240

European-Finnish (FIN) AF: 0.228 AC: 10000 AN: 43916

Middle Eastern (MID) AF: 0.316 AC: 1186 AN: 3750

European-Non Finnish (NFE) AF: 0.295 AC: 268502 AN: 910742

Other (OTH) AF: 0.322 AC: 16670 AN: 51762

GnomAD4 genome AF: 0.346 AC: 52642 AN: 151994 Hom.: 9527 Cov.: 32 AF XY: 0.344 AC XY: 25560 AN XY: 74284

African (AFR) AF: 0.455 AC: 18853 AN: 41448

American (AMR) AF: 0.375 AC: 5727 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1195 AN: 3466

East Asian (EAS) AF: 0.347 AC: 1788 AN: 5156

South Asian (SAS) AF: 0.305 AC: 1473 AN: 4826

European-Finnish (FIN) AF: 0.221 AC: 2333 AN: 10564

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20041 AN: 67946

Other (OTH) AF: 0.368 AC: 777 AN: 2110

Alfa AF: 0.318 Hom.: 1827

Bravo AF: 0.362

Asia WGS AF: 0.347 AC: 1206 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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 59% of patients studied by a panel of primary immunodeficiencies. Number of patients: 52. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.053
DANN	Benign	0.69
PhyloP100		-2.2
PromoterAI		0.0024	Neutral
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: rs3212714; hg19: chr19-17954947;