19-17846500-T-C

Variant names:

• chr19-17846500-T-C
• rs2110586
• NM_000215.4:c.-14+1446A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000215.4(JAK3):​c.-14+1446A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.856 in 152,178 control chromosomes in the GnomAD database, including 56,021 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.86 (56021 hom., cov: 32)
• Consequence: JAK3 NM_000215.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.995
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK3	NM_000215.4	c.-14+1446A>G		intron_variant	Intron 1 of 23	ENST00000458235.7	NP_000206.2
JAK3	NM_001440439.1	c.-45+1446A>G		intron_variant	Intron 1 of 23		NP_001427368.1
JAK3	XM_011527991.3	c.-14+1446A>G		intron_variant	Intron 1 of 13		XP_011526293.2
JAK3	XR_007066796.1	n.37+1446A>G		intron_variant	Intron 1 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK3	ENST00000458235.7	c.-14+1446A>G		intron_variant	Intron 1 of 23	5	NM_000215.4	ENSP00000391676.1

Frequencies

GnomAD3 genomes AF: 0.856 AC: 130194 AN: 152060 Hom.: 55969 Cov.: 32

Gnomad AFR AF: 0.906

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.901

Gnomad ASJ AF: 0.874

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.887

Gnomad FIN AF: 0.852

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.864

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.856 AC: 130304 AN: 152178 Hom.: 56021 Cov.: 32 AF XY: 0.860 AC XY: 63954 AN XY: 74392

African (AFR) AF: 0.906 AC: 37640 AN: 41552

American (AMR) AF: 0.901 AC: 13762 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.874 AC: 3034 AN: 3470

East Asian (EAS) AF: 0.998 AC: 5177 AN: 5186

South Asian (SAS) AF: 0.886 AC: 4264 AN: 4814

European-Finnish (FIN) AF: 0.852 AC: 9017 AN: 10580

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.805 AC: 54725 AN: 67988

Other (OTH) AF: 0.866 AC: 1830 AN: 2114

Alfa AF: 0.828 Hom.: 116288

Bravo AF: 0.863

Asia WGS AF: 0.940 AC: 3270 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.9
DANN	Benign	0.82
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism (auto)

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: rs2110586; hg19: chr19-17957309;