19-17841400-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 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.

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK3	NM_000215.4	c.1131C>A	p.His377Gln	missense_variant	8/24	ENST00000458235.7
JAK3	XM_047438786.1	c.1131C>A	p.His377Gln	missense_variant	8/24
JAK3	XM_011527991.3	c.1131C>A	p.His377Gln	missense_variant	8/14
JAK3	XR_007066796.1	n.1181C>A		non_coding_transcript_exon_variant	8/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK3	ENST00000458235.7	c.1131C>A	p.His377Gln	missense_variant	8/24	5	NM_000215.4	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;D;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.54	T;.;T
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.2	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.8	D;D;D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.98	D;D;P
Vest4		0.53
MutPred		0.77		Gain of relative solvent accessibility (P = 0.2629);Gain of relative solvent accessibility (P = 0.2629);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs55802448; hg19: chr19-17952209;