19-17842546-T-G

Variant names:

• chr19-17842546-T-G
• rs56269787
• NM_000215.4:c.631A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000215.4(JAK3):​c.631A>C​(p.Arg211Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,587,866 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (12 hom.)
• Consequence: JAK3 NM_000215.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.584
• 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=-0.74).
• BP6: Variant 19-17842546-T-G is Benign according to our data. Variant chr19-17842546-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 380482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.584 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00223 (340/152284) while in subpopulation NFE AF = 0.00425 (289/68004). AF 95% confidence interval is 0.00385. There are 1 homozygotes in GnomAd4. There are 147 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.631A>C	p.Arg211Arg	synonymous	Exon 6 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.631A>C	p.Arg211Arg	synonymous	Exon 6 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.631A>C	p.Arg211Arg	synonymous	Exon 6 of 24	ENSP00000391676.1	P52333-1
	JAK3	ENST00000527670.5	TSL:1	c.631A>C	p.Arg211Arg	synonymous	Exon 5 of 23	ENSP00000432511.1	P52333-1
	JAK3	ENST00000534444.1	TSL:1	c.631A>C	p.Arg211Arg	synonymous	Exon 6 of 23	ENSP00000436421.1	P52333-2

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 340 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00425

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00192 AC: 380 AN: 197830 AF XY: 0.00196

Gnomad AFR exome AF: 0.00115

Gnomad AMR exome AF: 0.000170

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000630

Gnomad NFE exome AF: 0.00413

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.00389 AC: 5589 AN: 1435582 Hom.: 12 Cov.: 37 AF XY: 0.00385 AC XY: 2739 AN XY: 712056

African (AFR) AF: 0.000667 AC: 22 AN: 32980

American (AMR) AF: 0.000271 AC: 11 AN: 40524

Ashkenazi Jewish (ASJ) AF: 0.000663 AC: 17 AN: 25622

East Asian (EAS) AF: 0.00 AC: 0 AN: 38400

South Asian (SAS) AF: 0.00 AC: 0 AN: 82896

European-Finnish (FIN) AF: 0.000677 AC: 34 AN: 50218

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5736

European-Non Finnish (NFE) AF: 0.00487 AC: 5353 AN: 1099806

Other (OTH) AF: 0.00254 AC: 151 AN: 59400

GnomAD4 genome AF: 0.00223 AC: 340 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.00197 AC XY: 147 AN XY: 74456

African (AFR) AF: 0.00101 AC: 42 AN: 41568

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00425 AC: 289 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00220

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	9.2
DANN	Benign	0.66
PhyloP100		0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs56269787; hg19: chr19-17953355;