19-17826905-G-T

Position:

• chr19-17826905-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000215.4(JAK3):​c.3213C>A​(p.His1071Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0490

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40615344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK3	NM_000215.4	c.3213C>A	p.His1071Gln	missense_variant	24/24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1	c.3213C>A	p.His1071Gln	missense_variant	24/24		XP_047294742.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.3213C>A	p.His1071Gln	missense_variant	24/24	5	NM_000215.4	ENSP00000391676	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000408 AC: 1 AN: 244838 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457224 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724926

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.90
DANN	Benign	0.94
DEOGEN2	Uncertain	0.73	D;D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.52	T;.
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.22	N;N
MutationTaster	Benign	0.65	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.28
Sift	Benign	0.12	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.012	B;B
Vest4		0.25
MutPred		0.74		Gain of ubiquitination at K1075 (P = 0.0556);Gain of ubiquitination at K1075 (P = 0.0556);
MVP		0.77
MPC		0.39
ClinPred		0.078	T
GERP RS		-7.2
Varity_R		0.45
gMVP		0.43

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: rs757910571; hg19: chr19-17937714;