19-17841400-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000215.4(JAK3):​c.1131C>A​(p.His377Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H377H) has been classified as Likely benign. The gene JAK3 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Not reported in ClinVar
• 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Specifications for JAK3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1131C>A	p.His377Gln	missense	Exon 8 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.1131C>A	p.His377Gln	missense	Exon 8 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.1131C>A	p.His377Gln	missense	Exon 8 of 24	ENSP00000391676.1	P52333-1
	JAK3	ENST00000527670.5	TSL:1	c.1131C>A	p.His377Gln	missense	Exon 7 of 23	ENSP00000432511.1	P52333-1
	JAK3	ENST00000534444.1	TSL:1	c.1131C>A	p.His377Gln	missense	Exon 8 of 23	ENSP00000436421.1	P52333-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1398596 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 690282

African (AFR) AF: 0.00 AC: 0 AN: 31844

American (AMR) AF: 0.00 AC: 0 AN: 35934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25192

East Asian (EAS) AF: 0.00 AC: 0 AN: 36062

South Asian (SAS) AF: 0.00 AC: 0 AN: 79488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080418

Other (OTH) AF: 0.00 AC: 0 AN: 58076

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		-1.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.025	D
Polyphen		0.98	D
Vest4		0.53
MutPred		0.77		Gain of relative solvent accessibility (P = 0.2629)
MVP		0.75
MPC		0.61
ClinPred		0.99	D
GERP RS		-5.2
Varity_R		0.80
gMVP		0.80
Mutation Taster		=60/40	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;