rs2254002

Positions:

• chr1-64835986-C-A
• chr1-64835986-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002227.4(JAK1):​c.3258+112G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 675,290 control chromosomes in the GnomAD database, including 68,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.52 (23604 hom., cov: 32)
  • Exomes 𝑓: 0.40 (45151 hom.)
• Consequence: JAK1 NM_002227.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.845

Genes affected

JAK1 (HGNC:6190): (Janus kinase 1) This gene encodes a membrane protein that is a member of a class of protein-tyrosine kinases (PTK) characterized by the presence of a second phosphotransferase-related domain immediately N-terminal to the PTK domain. The encoded kinase phosphorylates STAT proteins (signal transducers and activators of transcription) and plays a key role in interferon-alpha/beta, interferon-gamma, and cytokine signal transduction. This gene plays a crucial role in effecting the expression of genes that mediate inflammation, epithelial remodeling, and metastatic cancer progression. This gene is a key component of the interleukin-6 (IL-6)/JAK1/STAT3 immune and inflammation response and is a therapeutic target for alleviating cytokine storms. The kinase activity of this gene is directly inhibited by the suppressor of cytokine signalling 1 (SOCS1) protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-64835986-C-A is Benign according to our data. Variant chr1-64835986-C-A is described in ClinVar as [Benign]. Clinvar id is 2688493.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK1	NM_002227.4	c.3258+112G>T		intron_variant		ENST00000342505.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK1	ENST00000342505.5	c.3258+112G>T		intron_variant		5	NM_002227.4	A1

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78104 AN: 151734 Hom.: 23546 Cov.: 32

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.484

GnomAD4 exome AF: 0.401 AC: 210097 AN: 523438 Hom.: 45151 AF XY: 0.395 AC XY: 110086 AN XY: 278370

Gnomad4 AFR exome AF: 0.841

Gnomad4 AMR exome AF: 0.513

Gnomad4 ASJ exome AF: 0.470

Gnomad4 EAS exome AF: 0.594

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.404

Gnomad4 NFE exome AF: 0.353

Gnomad4 OTH exome AF: 0.430

GnomAD4 genome AF: 0.515 AC: 78227 AN: 151852 Hom.: 23604 Cov.: 32 AF XY: 0.515 AC XY: 38174 AN XY: 74168

Gnomad4 AFR AF: 0.840

Gnomad4 AMR AF: 0.470

Gnomad4 ASJ AF: 0.481

Gnomad4 EAS AF: 0.612

Gnomad4 SAS AF: 0.356

Gnomad4 FIN AF: 0.420

Gnomad4 NFE AF: 0.351

Gnomad4 OTH AF: 0.489

Alfa AF: 0.470 Hom.: 2378

Bravo AF: 0.538

Asia WGS AF: 0.525 AC: 1824 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.40

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: rs2254002; hg19: chr1-65301669; COSMIC: COSV53810753; COSMIC: COSV53810753;