rs3212716

Variant names:

• chr19-17843788-C-G
• rs3212716
• NM_000215.4:c.297G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-17843788-C-G
• chr19-17843788-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000215.4(JAK3):​c.297G>C​(p.Leu99Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00457 in 1,613,464 control chromosomes in the GnomAD database, including 323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L99L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.025 (168 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (155 hom.)
• Consequence: JAK3 NM_000215.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.897
• 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: G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-17843788-C-G is Benign according to our data. Variant chr19-17843788-C-G is described in ClinVar as Benign. ClinVar VariationId is 137600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.897 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.084 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.297G>C	p.Leu99Leu	synonymous	Exon 3 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.297G>C	p.Leu99Leu	synonymous	Exon 3 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.297G>C	p.Leu99Leu	synonymous	Exon 3 of 24	ENSP00000391676.1	P52333-1
	JAK3	ENST00000527670.5	TSL:1	c.297G>C	p.Leu99Leu	synonymous	Exon 2 of 23	ENSP00000432511.1	P52333-1
	JAK3	ENST00000534444.1	TSL:1	c.297G>C	p.Leu99Leu	synonymous	Exon 3 of 23	ENSP00000436421.1	P52333-2

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3736 AN: 151926 Hom.: 168 Cov.: 32

Gnomad AFR AF: 0.0863

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00865

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0125

GnomAD2 exomes AF: 0.00656 AC: 1647 AN: 251216 AF XY: 0.00439

Gnomad AFR exome AF: 0.0904

Gnomad AMR exome AF: 0.00405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00249 AC: 3632 AN: 1461420 Hom.: 155 Cov.: 33 AF XY: 0.00210 AC XY: 1530 AN XY: 727040

African (AFR) AF: 0.0899 AC: 3010 AN: 33478

American (AMR) AF: 0.00472 AC: 211 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53012

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0000522 AC: 58 AN: 1111962

Other (OTH) AF: 0.00530 AC: 320 AN: 60388

GnomAD4 genome AF: 0.0246 AC: 3746 AN: 152044 Hom.: 168 Cov.: 32 AF XY: 0.0233 AC XY: 1733 AN XY: 74318

African (AFR) AF: 0.0864 AC: 3577 AN: 41420

American (AMR) AF: 0.00864 AC: 132 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67980

Other (OTH) AF: 0.0123 AC: 26 AN: 2106

Alfa AF: 0.00161 Hom.: 1

Bravo AF: 0.0284

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.4
DANN	Benign	0.55
PhyloP100		0.90
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: rs3212716; hg19: chr19-17954597;