NM_002227.4:c.2404-125C>T

Variant names:

• chr1-64841726-G-A
• rs310247
• NM_002227.4:c.2404-125C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002227.4(JAK1):​c.2404-125C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 947,774 control chromosomes in the GnomAD database, including 111,695 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.56 (26358 hom., cov: 32)
  • Exomes 𝑓: 0.45 (85337 hom.)
• Consequence: JAK1 NM_002227.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.450
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• autoinflammation, immune dysregulation, and eosinophilia

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-64841726-G-A is Benign according to our data. Variant chr1-64841726-G-A is described in ClinVar as Benign. ClinVar VariationId is 2628129.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK1	NM_002227.4	c.2404-125C>T		intron_variant	Intron 17 of 24	ENST00000342505.5	NP_002218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5	c.2404-125C>T		intron_variant	Intron 17 of 24	5	NM_002227.4	ENSP00000343204.4

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85365 AN: 151978 Hom.: 26290 Cov.: 32

Gnomad AFR AF: 0.822

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.603

Gnomad ASJ AF: 0.527

Gnomad EAS AF: 0.611

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.529

GnomAD4 exome AF: 0.455 AC: 361739 AN: 795678 Hom.: 85337 AF XY: 0.453 AC XY: 186643 AN XY: 411794

African (AFR) AF: 0.830 AC: 16248 AN: 19574

American (AMR) AF: 0.673 AC: 20495 AN: 30468

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 9406 AN: 18068

East Asian (EAS) AF: 0.585 AC: 20259 AN: 34614

South Asian (SAS) AF: 0.455 AC: 27964 AN: 61478

European-Finnish (FIN) AF: 0.447 AC: 16642 AN: 37190

Middle Eastern (MID) AF: 0.419 AC: 1131 AN: 2698

European-Non Finnish (NFE) AF: 0.418 AC: 231427 AN: 553816

Other (OTH) AF: 0.481 AC: 18167 AN: 37772

GnomAD4 genome AF: 0.562 AC: 85503 AN: 152096 Hom.: 26358 Cov.: 32 AF XY: 0.563 AC XY: 41881 AN XY: 74342

African (AFR) AF: 0.823 AC: 34148 AN: 41510

American (AMR) AF: 0.603 AC: 9218 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 1829 AN: 3468

East Asian (EAS) AF: 0.611 AC: 3149 AN: 5154

South Asian (SAS) AF: 0.449 AC: 2162 AN: 4820

European-Finnish (FIN) AF: 0.457 AC: 4832 AN: 10572

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.420 AC: 28545 AN: 67974

Other (OTH) AF: 0.534 AC: 1127 AN: 2112

Alfa AF: 0.440 Hom.: 7856

Bravo AF: 0.588

Asia WGS AF: 0.572 AC: 1988 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 70% of patients studied by a panel of primary immunodeficiencies. Number of patients: 67. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.0
DANN	Benign	0.50
PhyloP100		-0.45
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: rs310247; hg19: chr1-65307409;