NM_000215.4:c.*1038A>G

Variant names:

• chr19-17825705-T-C
• rs373917722
• NM_000215.4:c.*1038A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000215.4(JAK3):​c.*1038A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 167,184 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (0 hom.)
• Consequence: JAK3 NM_000215.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.299
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 19-17825705-T-C is Benign according to our data. Variant chr19-17825705-T-C is described in ClinVar as Benign. ClinVar VariationId is 328476.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00139 (211/151924) while in subpopulation EAS AF = 0.0322 (165/5122). AF 95% confidence interval is 0.0282. There are 4 homozygotes in GnomAd4. There are 112 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.*1038A>G		3_prime_UTR	Exon 24 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.*1038A>G		3_prime_UTR	Exon 24 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.*1038A>G		3_prime_UTR	Exon 24 of 24	ENSP00000391676.1	P52333-1
	JAK3	ENST00000696967.1		n.3590A>G		non_coding_transcript_exon	Exon 19 of 19
	JAK3	ENST00000696968.1		n.1646A>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 213 AN: 151806 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0325

Gnomad SAS AF: 0.00229

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00192

GnomAD4 exome AF: 0.00197 AC: 30 AN: 15260 Hom.: 0 Cov.: 0 AF XY: 0.00140 AC XY: 10 AN XY: 7154

African (AFR) AF: 0.00 AC: 0 AN: 456

American (AMR) AF: 0.00 AC: 0 AN: 302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1004

East Asian (EAS) AF: 0.00757 AC: 27 AN: 3566

South Asian (SAS) AF: 0.00 AC: 0 AN: 136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 92

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8552

Other (OTH) AF: 0.00263 AC: 3 AN: 1140

GnomAD4 genome AF: 0.00139 AC: 211 AN: 151924 Hom.: 4 Cov.: 31 AF XY: 0.00151 AC XY: 112 AN XY: 74268

African (AFR) AF: 0.000579 AC: 24 AN: 41458

American (AMR) AF: 0.000394 AC: 6 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.0322 AC: 165 AN: 5122

South Asian (SAS) AF: 0.00229 AC: 11 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67930

Other (OTH) AF: 0.00190 AC: 4 AN: 2102

Alfa AF: 0.000624 Hom.: 0

Bravo AF: 0.00131

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	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	-1.0
CADD	Benign	1.4
DANN	Benign	0.065
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism

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: rs373917722; hg19: chr19-17936514;