NM_000215.4:c.2164G>C

Variant names:

• chr19-17834887-C-G
• rs3213409
• NM_000215.4:c.2164G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000215.4(JAK3):​c.2164G>C​(p.Val722Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V722I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.04
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40881687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.2164G>C	p.Val722Leu	missense_variant	Exon 16 of 24	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.2164G>C	p.Val722Leu	missense_variant	Exon 16 of 24		NP_001427368.1
JAK3	XR_007066796.1	n.2214G>C		non_coding_transcript_exon_variant	Exon 16 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.2164G>C	p.Val722Leu	missense_variant	Exon 16 of 24	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Uncertain	0.42	T;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.73	T;.;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.030	N;N;N
PhyloP100		3.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.94	N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0040	D;D;D
Sift4G	Benign	0.062	T;T;T
Polyphen		0.0030	B;B;B
Vest4		0.066
MutPred		0.92		Loss of glycosylation at S720 (P = 0.182);Loss of glycosylation at S720 (P = 0.182);Loss of glycosylation at S720 (P = 0.182);
MVP		0.43
MPC		0.51
ClinPred		0.41	T
GERP RS		0.25
Varity_R		0.15
gMVP		0.67
Mutation Taster		=98/2	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: rs3213409; hg19: chr19-17945696;