19-17831748-G-C

Position:

• chr19-17831748-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000215.4(JAK3):​c.2731C>G​(p.Arg911Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.72

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK3	NM_000215.4	c.2731C>G	p.Arg911Gly	missense_variant	20/24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1	c.2731C>G	p.Arg911Gly	missense_variant	20/24		XP_047294742.1
JAK3	XR_007066796.1	n.2866C>G		non_coding_transcript_exon_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.2731C>G	p.Arg911Gly	missense_variant	20/24	5	NM_000215.4	ENSP00000391676	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460188 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726428

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;D;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.78	N;N;N
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0070	D;D;D
Sift4G	Benign	0.092	T;T;T
Polyphen		0.0040	B;B;B
Vest4		0.79
MutPred		0.69		Loss of MoRF binding (P = 0.0149);Loss of MoRF binding (P = 0.0149);Loss of MoRF binding (P = 0.0149);
MVP		0.99
MPC		0.78
ClinPred		0.69	D
GERP RS		0.35
Varity_R		0.69
gMVP		0.96

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: rs587778417; hg19: chr19-17942557; COSMIC: COSV105940659;