rs7254346

Variant names:

• chr19-17847968-T-C
• rs7254346
• NM_000215.4:c.-36A>G

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.-36A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,036,266 control chromosomes in the GnomAD database, including 13,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (7265 hom., cov: 33)
  • Exomes 𝑓: 0.091 (6226 hom.)
• Consequence: JAK3 NM_000215.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.861
• Publications: 17 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-17847968-T-C is Benign according to our data. Variant chr19-17847968-T-C is described in ClinVar as Benign. ClinVar VariationId is 328525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.555 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	NM_000215.4	MANE Select	c.-36A>G		5_prime_UTR	Exon 1 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.-67A>G		5_prime_UTR	Exon 1 of 24	NP_001427368.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	ENST00000458235.7	TSL:5 MANE Select	c.-36A>G		5_prime_UTR	Exon 1 of 24	ENSP00000391676.1	P52333-1
	JAK3	ENST00000534444.1	TSL:1	c.-36A>G		5_prime_UTR	Exon 1 of 23	ENSP00000436421.1	P52333-2
	JAK3	ENST00000526008.6	TSL:2	n.-36A>G		non_coding_transcript_exon	Exon 1 of 25	ENSP00000513006.1	A0A0S2Z4R7

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33472 AN: 152060 Hom.: 7242 Cov.: 33

Gnomad AFR AF: 0.561

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0746

Gnomad OTH AF: 0.193

GnomAD4 exome AF: 0.0911 AC: 80578 AN: 884088 Hom.: 6226 Cov.: 29 AF XY: 0.0900 AC XY: 36732 AN XY: 408346

African (AFR) AF: 0.588 AC: 10447 AN: 17758

American (AMR) AF: 0.120 AC: 283 AN: 2352

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 866 AN: 8322

East Asian (EAS) AF: 0.212 AC: 2479 AN: 11688

South Asian (SAS) AF: 0.113 AC: 1919 AN: 16958

European-Finnish (FIN) AF: 0.0472 AC: 15 AN: 318

Middle Eastern (MID) AF: 0.0919 AC: 318 AN: 3462

European-Non Finnish (NFE) AF: 0.0763 AC: 60391 AN: 791666

Other (OTH) AF: 0.122 AC: 3860 AN: 31564

GnomAD4 genome AF: 0.220 AC: 33553 AN: 152178 Hom.: 7265 Cov.: 33 AF XY: 0.217 AC XY: 16178 AN XY: 74400

African (AFR) AF: 0.561 AC: 23298 AN: 41502

American (AMR) AF: 0.149 AC: 2281 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 359 AN: 3472

East Asian (EAS) AF: 0.222 AC: 1146 AN: 5168

South Asian (SAS) AF: 0.117 AC: 565 AN: 4830

European-Finnish (FIN) AF: 0.0325 AC: 345 AN: 10612

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0746 AC: 5071 AN: 68000

Other (OTH) AF: 0.196 AC: 415 AN: 2112

Alfa AF: 0.108 Hom.: 3232

Bravo AF: 0.243

Asia WGS AF: 0.206 AC: 715 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	T-B+ severe combined immunodeficiency due to JAK3 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.0
DANN	Benign	0.35
PhyloP100		-0.86
PromoterAI		-0.17	Neutral
Mutation Taster		=300/0	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: rs7254346; hg19: chr19-17958777;