rs2256298

chr1-64864999-G-Achr1-64864999-G-C

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.991-27C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,571,840 control chromosomes in the GnomAD database, including 61,036 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (10916 hom., cov: 32)
  • Exomes 𝑓: 0.26 (50120 hom.)
• Consequence: JAK1 NM_002227.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.181

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=-0.83).
• BP6: Variant 1-64864999-G-A is Benign according to our data. Variant chr1-64864999-G-A is described in ClinVar as [Benign]. Clinvar id is 2628145.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK1	NM_002227.4	c.991-27C>T		intron_variant		ENST00000342505.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK1	ENST00000342505.5	c.991-27C>T		intron_variant		5	NM_002227.4	A1

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53296 AN: 151904 Hom.: 10874 Cov.: 32

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.327

GnomAD3 exomes AF: 0.303 AC: 72948 AN: 240654 Hom.: 12284 AF XY: 0.290 AC XY: 38000 AN XY: 130834

Gnomad AFR exome AF: 0.574

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.311

Gnomad EAS exome AF: 0.333

Gnomad SAS exome AF: 0.240

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.257 AC: 364462 AN: 1419818 Hom.: 50120 Cov.: 25 AF XY: 0.255 AC XY: 180475 AN XY: 707950

Gnomad4 AFR exome AF: 0.587

Gnomad4 AMR exome AF: 0.460

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.303

Gnomad4 SAS exome AF: 0.235

Gnomad4 FIN exome AF: 0.237

Gnomad4 NFE exome AF: 0.238

Gnomad4 OTH exome AF: 0.269

GnomAD4 genome AF: 0.351 AC: 53400 AN: 152022 Hom.: 10916 Cov.: 32 AF XY: 0.351 AC XY: 26056 AN XY: 74312

Gnomad4 AFR AF: 0.571

Gnomad4 AMR AF: 0.402

Gnomad4 ASJ AF: 0.310

Gnomad4 EAS AF: 0.306

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.239

Gnomad4 NFE AF: 0.241

Gnomad4 OTH AF: 0.334

Alfa AF: 0.269 Hom.: 8096

Bravo AF: 0.375

Asia WGS AF: 0.308 AC: 1073 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

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 59% of patients studied by a panel of primary immunodeficiencies. Number of patients: 57. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.2
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2256298; hg19: chr1-65330682; COSMIC: COSV61087701; COSMIC: COSV61087701;