rs2072496

Variant names:

• chr19-17835245-G-A
• rs2072496
• NM_000215.4:c.1915-30C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-17835245-G-A
• chr19-17835245-G-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.1915-30C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,609,508 control chromosomes in the GnomAD database, including 10,585 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (959 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9626 hom.)
• Consequence: JAK3 NM_000215.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.40
• Publications: 19 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=-0.93).
• BP6: Variant 19-17835245-G-A is Benign according to our data. Variant chr19-17835245-G-A is described in ClinVar as [Benign]. Clinvar id is 632862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.1915-30C>T		intron_variant	Intron 14 of 23	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.1915-30C>T		intron_variant	Intron 14 of 23		NP_001427368.1
JAK3	XR_007066796.1	n.1965-30C>T		intron_variant	Intron 14 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.1915-30C>T		intron_variant	Intron 14 of 23	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15779 AN: 152174 Hom.: 960 Cov.: 32

Gnomad AFR AF: 0.0985

Gnomad AMI AF: 0.0989

Gnomad AMR AF: 0.0930

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.0545

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0971

GnomAD2 exomes AF: 0.113 AC: 27237 AN: 242044 AF XY: 0.114

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.0895

Gnomad ASJ exome AF: 0.0571

Gnomad EAS exome AF: 0.276

Gnomad FIN exome AF: 0.0612

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.110 AC: 160496 AN: 1457218 Hom.: 9626 Cov.: 39 AF XY: 0.111 AC XY: 80326 AN XY: 724770

African (AFR) AF: 0.0989 AC: 3306 AN: 33436

American (AMR) AF: 0.0882 AC: 3923 AN: 44460

Ashkenazi Jewish (ASJ) AF: 0.0553 AC: 1440 AN: 26044

East Asian (EAS) AF: 0.261 AC: 10337 AN: 39628

South Asian (SAS) AF: 0.138 AC: 11923 AN: 86120

European-Finnish (FIN) AF: 0.0584 AC: 2979 AN: 51008

Middle Eastern (MID) AF: 0.130 AC: 720 AN: 5544

European-Non Finnish (NFE) AF: 0.107 AC: 118762 AN: 1110736

Other (OTH) AF: 0.118 AC: 7106 AN: 60242

GnomAD4 genome AF: 0.104 AC: 15784 AN: 152290 Hom.: 959 Cov.: 32 AF XY: 0.102 AC XY: 7596 AN XY: 74462

African (AFR) AF: 0.0984 AC: 4087 AN: 41548

American (AMR) AF: 0.0930 AC: 1424 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 200 AN: 3472

East Asian (EAS) AF: 0.271 AC: 1403 AN: 5178

South Asian (SAS) AF: 0.140 AC: 678 AN: 4828

European-Finnish (FIN) AF: 0.0545 AC: 579 AN: 10624

Middle Eastern (MID) AF: 0.113 AC: 33 AN: 292

European-Non Finnish (NFE) AF: 0.104 AC: 7084 AN: 68020

Other (OTH) AF: 0.0975 AC: 206 AN: 2112

Alfa AF: 0.105 Hom.: 857

Bravo AF: 0.106

Asia WGS AF: 0.184 AC: 639 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 18. Only high quality variants are reported. -

Nov 28, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The JAK3 c.1915-30C>T variant involves the alteration of a non-conserved intronic nucleotide and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may alter ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 29715/269050 control chromosomes (1955 homozygotes)(gnomAD) at a frequency of 0.1104442, which is approximately 102 times the estimated maximal expected allele frequency of a pathogenic JAK3 variant (0.0010801), suggesting this variant is likely a benign polymorphism. This variant has been reported in 2 patients with SCID (Walshe 2009), however without strong evidence for causality. Taken together, this variant is classified as benign. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.4
DANN	Benign	0.48
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2072496; hg19: chr19-17946054; COSMIC: COSV71685824; COSMIC: COSV71685824;