NM_000215.4:c.1830G>T

Variant names:

• chr19-17836008-C-A
• NM_000215.4:c.1830G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000215.4(JAK3):​c.1830G>T​(p.Met610Ile) 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 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: 0.0000014 (0 hom.)
• Consequence: JAK3 NM_000215.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.41

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.

• PM1: In a domain Protein kinase 1 (size 260) in uniprot entity JAK3_HUMAN there are 11 pathogenic changes around while only 3 benign (79%) in NM_000215.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16206694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.1830G>T	p.Met610Ile	missense_variant	Exon 14 of 24	ENST00000458235.7	NP_000206.2
JAK3	XM_047438786.1	c.1830G>T	p.Met610Ile	missense_variant	Exon 14 of 24		XP_047294742.1
JAK3	XR_007066796.1	n.1880G>T		non_coding_transcript_exon_variant	Exon 14 of 20
JAK3	XM_011527991.3	c.*909G>T		downstream_gene_variant			XP_011526293.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.1830G>T	p.Met610Ile	missense_variant	Exon 14 of 24	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461800 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727190

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: 0.00000180

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	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.0010
DANN	Benign	0.68
DEOGEN2	Benign	0.35	T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.69	T;.;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L;L;L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.30	N;N;N
REVEL	Benign	0.082
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0040	B;B;B
Vest4		0.18
MutPred		0.51		Gain of catalytic residue at M610 (P = 0.001);Gain of catalytic residue at M610 (P = 0.001);Gain of catalytic residue at M610 (P = 0.001);
MVP		0.52
MPC		0.53
ClinPred		0.19	T
GERP RS		-9.9
Varity_R		0.051
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-17946817;