NM_002227.4:c.3369+4T>G

Variant names:

• chr1-64835392-A-C
• rs751396065
• NM_002227.4:c.3369+4T>G

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The NM_002227.4(JAK1):c.3369+4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: JAK1 NM_002227.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002228
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.505
• Publications: 0 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: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002227.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	JAK1 NM_002227.4	MANE Select	c.3369+4T>G	splice_regionintron	Intron 24 of 24	Prot: NP_002218.2 UniProt:
	JAK1 NM_001320923.2		c.3369+4T>G	splice_regionintron	Intron 25 of 25	Prot: NP_001307852.1 UniProt:
	JAK1 NM_001321852.2		c.3369+4T>G	splice_regionintron	Intron 24 of 24	Prot: NP_001308781.1 UniProt:

JAK1 NM_002227.4

MANE Select

HGVSc / HGVSpc.3369+4T>G

Exon rankIntron 24 of 24

splice_regionintron

Prot: NP_002218.2UniProt: P23458

JAK1 NM_001320923.2

HGVSc / HGVSpc.3369+4T>G

Exon rankIntron 25 of 25

splice_regionintron

Prot: NP_001307852.1UniProt: P23458

JAK1 NM_001321852.2

HGVSc / HGVSpc.3369+4T>G

Exon rankIntron 24 of 24

splice_regionintron

Prot: NP_001308781.1UniProt: P23458

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	JAK1 ENST00000342505.5	TSL:5MANE Select	c.3369+4T>G	splice_regionintron	Intron 24 of 24	Prot: ENSP00000343204.4 UniProt:
	JAK1 ENST00000671929.2		c.3369+4T>G	splice_regionintron	Intron 25 of 25	Prot: ENSP00000500485.1 UniProt:
	JAK1 ENST00000671954.2		c.3369+4T>G	splice_regionintron	Intron 25 of 25	Prot: ENSP00000500841.1 UniProt:

JAK1 ENST00000342505.5

TSL:5MANE Select

HGVSc / HGVSpc.3369+4T>G

Exon rankIntron 24 of 24

splice_regionintron

Prot: ENSP00000343204.4UniProt: P23458

JAK1 ENST00000671929.2

HGVSc / HGVSpc.3369+4T>G

Exon rankIntron 25 of 25

splice_regionintron

Prot: ENSP00000500485.1UniProt: P23458

JAK1 ENST00000671954.2

HGVSc / HGVSpc.3369+4T>G

Exon rankIntron 25 of 25

splice_regionintron

Prot: ENSP00000500841.1UniProt: P23458

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:22
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	1.2
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.8
DANN	Benign	0.73
GPN-Star LLR	N/A	-3.5
GPN-Star score	N/A	3.5
PhyloP100	Benign	-0.51

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.036
Pangolin (max)	Benign	0.11
Pangolin loss	Benign	0.11	Position offset: 4
SpliceAI score (max)	Benign	0.11	Details are displayed if max score is > 0.2

Showing 5 of 5 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs751396065;

hg19: chr1-65301075;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar