19-17843446-G-T

Variant names:

• chr19-17843446-G-T
• NM_000215.4:c.354C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000215.4(JAK3):​c.354C>A​(p.Phe118Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,802 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F118F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.770

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 4 ACMG points.

• PM1: In a region_of_interest Interaction with cytokine/interferon/growth hormone receptors (size 222) in uniprot entity JAK3_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000215.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.354C>A	p.Phe118Leu	missense_variant	Exon 4 of 24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1	c.354C>A	p.Phe118Leu	missense_variant	Exon 4 of 24		XP_047294742.1
JAK3	XM_011527991.3	c.354C>A	p.Phe118Leu	missense_variant	Exon 4 of 14		XP_011526293.2
JAK3	XR_007066796.1	n.404C>A		non_coding_transcript_exon_variant	Exon 4 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.354C>A	p.Phe118Leu	missense_variant	Exon 4 of 24	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447802 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719256

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000388

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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	5.8
DANN	Benign	0.91
DEOGEN2	Benign	0.37	T;T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.64	T;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.5	M;M;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.52	T;T;T
Sift4G	Benign	0.60	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.44
MutPred		0.51		Gain of catalytic residue at F118 (P = 0.0624);Gain of catalytic residue at F118 (P = 0.0624);Gain of catalytic residue at F118 (P = 0.0624);
MVP		0.69
MPC		1.4
ClinPred		0.83	D
GERP RS		-9.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.077
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-17954255;