chr19-17841400-G-A

Variant names:

• chr19-17841400-G-A
• rs55802448
• NM_000215.4:c.1131C>T

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.1131C>T​(p.His377His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,550,872 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (29 hom.)
• Consequence: JAK3 NM_000215.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.86
• Publications: 3 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, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 19-17841400-G-A is Benign according to our data. Variant chr19-17841400-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 385188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.86 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00153 (233/152276) while in subpopulation SAS AF = 0.0174 (84/4830). AF 95% confidence interval is 0.0144. There are 4 homozygotes in GnomAd4. There are 139 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	NM_000215.4	MANE Select	c.1131C>T	p.His377His	synonymous	Exon 8 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.1131C>T	p.His377His	synonymous	Exon 8 of 24	NP_001427368.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	ENST00000458235.7	TSL:5 MANE Select	c.1131C>T	p.His377His	synonymous	Exon 8 of 24	ENSP00000391676.1
	JAK3	ENST00000527670.5	TSL:1	c.1131C>T	p.His377His	synonymous	Exon 7 of 23	ENSP00000432511.1
	JAK3	ENST00000534444.1	TSL:1	c.1131C>T	p.His377His	synonymous	Exon 8 of 23	ENSP00000436421.1

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 152158 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00305 AC: 476 AN: 155910 AF XY: 0.00407

Gnomad AFR exome AF: 0.000222

Gnomad AMR exome AF: 0.000200

Gnomad ASJ exome AF: 0.00399

Gnomad EAS exome AF: 0.0000868

Gnomad FIN exome AF: 0.000152

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.00201 AC: 2815 AN: 1398596 Hom.: 29 Cov.: 35 AF XY: 0.00244 AC XY: 1686 AN XY: 690282

African (AFR) AF: 0.0000942 AC: 3 AN: 31844

American (AMR) AF: 0.000334 AC: 12 AN: 35934

Ashkenazi Jewish (ASJ) AF: 0.00397 AC: 100 AN: 25192

East Asian (EAS) AF: 0.0000277 AC: 1 AN: 36062

South Asian (SAS) AF: 0.0155 AC: 1229 AN: 79488

European-Finnish (FIN) AF: 0.000218 AC: 10 AN: 45900

Middle Eastern (MID) AF: 0.00264 AC: 15 AN: 5682

European-Non Finnish (NFE) AF: 0.00121 AC: 1306 AN: 1080418

Other (OTH) AF: 0.00239 AC: 139 AN: 58076

GnomAD4 genome AF: 0.00153 AC: 233 AN: 152276 Hom.: 4 Cov.: 31 AF XY: 0.00187 AC XY: 139 AN XY: 74442

African (AFR) AF: 0.000265 AC: 11 AN: 41560

American (AMR) AF: 0.000523 AC: 8 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5170

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00151 AC: 103 AN: 68008

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00150 Hom.: 0

Bravo AF: 0.00121

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	T-B+ severe combined immunodeficiency due to JAK3 deficiency (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.6
DANN	Benign	0.90
PhyloP100		-1.9
Mutation Taster		=99/1	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: rs55802448; hg19: chr19-17952209; COSMIC: COSV71686029; COSMIC: COSV71686029;