rs310216

Positions:

• chr1-64850992-G-A

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.1649-82C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 908,368 control chromosomes in the GnomAD database, including 38,936 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (10831 hom., cov: 32)
  • Exomes 𝑓: 0.26 (28105 hom.)
• Consequence: JAK1 NM_002227.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.197

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]

JAK1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-64850992-G-A is Benign according to our data. Variant chr1-64850992-G-A is described in ClinVar as [Benign]. Clinvar id is 2628196.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK1	NM_002227.4	c.1649-82C>T		intron_variant		ENST00000342505.5	NP_002218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5	c.1649-82C>T		intron_variant		5	NM_002227.4	ENSP00000343204.4

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52800 AN: 151932 Hom.: 10793 Cov.: 32

Gnomad AFR AF: 0.578

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.331

GnomAD4 exome AF: 0.264 AC: 199858 AN: 756318 Hom.: 28105 AF XY: 0.261 AC XY: 103646 AN XY: 396802

Gnomad4 AFR exome AF: 0.584

Gnomad4 AMR exome AF: 0.345

Gnomad4 ASJ exome AF: 0.354

Gnomad4 EAS exome AF: 0.293

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.276

Gnomad4 NFE exome AF: 0.241

Gnomad4 OTH exome AF: 0.281

GnomAD4 genome AF: 0.348 AC: 52897 AN: 152050 Hom.: 10831 Cov.: 32 AF XY: 0.347 AC XY: 25759 AN XY: 74316

Gnomad4 AFR AF: 0.578

Gnomad4 AMR AF: 0.306

Gnomad4 ASJ AF: 0.357

Gnomad4 EAS AF: 0.294

Gnomad4 SAS AF: 0.228

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.338

Alfa AF: 0.274 Hom.: 6090

Bravo AF: 0.362

Asia WGS AF: 0.309 AC: 1074 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 45% of patients studied by a panel of primary immunodeficiencies. Number of patients: 43. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.0
DANN	Benign	0.66

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: rs310216; hg19: chr1-65316675;