chr19-17825546-C-T

Variant names:

• chr19-17825546-C-T
• rs3213415
• NM_000215.4:c.*1197G>A

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.*1197G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 199,536 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0073 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0081 (1 hom.)
• Consequence: JAK3 NM_000215.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.400
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-17825546-C-T is Benign according to our data. Variant chr19-17825546-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 328474.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00734 (1118/152262) while in subpopulation AMR AF = 0.0111 (170/15278). AF 95% confidence interval is 0.0103. There are 8 homozygotes in GnomAd4. There are 530 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.*1197G>A		3_prime_UTR	Exon 24 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.*1197G>A		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.*1197G>A		3_prime_UTR	Exon 24 of 24	ENSP00000391676.1	P52333-1
	JAK3	ENST00000696967.1		n.3749G>A		non_coding_transcript_exon	Exon 19 of 19
	JAK3	ENST00000696968.1		n.1805G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00735 AC: 1118 AN: 152144 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00766

GnomAD4 exome AF: 0.00812 AC: 384 AN: 47274 Hom.: 1 Cov.: 0 AF XY: 0.00876 AC XY: 192 AN XY: 21918

African (AFR) AF: 0.00158 AC: 3 AN: 1896

American (AMR) AF: 0.00317 AC: 4 AN: 1262

Ashkenazi Jewish (ASJ) AF: 0.00709 AC: 21 AN: 2962

East Asian (EAS) AF: 0.00 AC: 0 AN: 7860

South Asian (SAS) AF: 0.00503 AC: 2 AN: 398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28

Middle Eastern (MID) AF: 0.0211 AC: 6 AN: 284

European-Non Finnish (NFE) AF: 0.0107 AC: 307 AN: 28622

Other (OTH) AF: 0.0103 AC: 41 AN: 3962

GnomAD4 genome AF: 0.00734 AC: 1118 AN: 152262 Hom.: 8 Cov.: 31 AF XY: 0.00712 AC XY: 530 AN XY: 74456

African (AFR) AF: 0.00207 AC: 86 AN: 41556

American (AMR) AF: 0.0111 AC: 170 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4828

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10608

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0110 AC: 748 AN: 68022

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.00821 Hom.: 0

Bravo AF: 0.00739

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	-0.84
CADD	Benign	2.6
DANN	Benign	0.84
PhyloP100		0.40
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: rs3213415; hg19: chr19-17936355;