dbSNP rs751396065: JAK1:c.3369+4T>G (chr1-64835392-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is 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

Variant links:

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

JAK1 links:

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new If you want to explore the variant's impact on the transcript NM_002227.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

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

Show applied only (2)

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

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: P23458
JAK1 NM_001320923.2		c.3369+4T>G	splice_regionintron	Intron 25 of 25	Prot: NP_001307852.1 UniProt: P23458
JAK1 NM_001321852.2		c.3369+4T>G	splice_regionintron	Intron 24 of 24	Prot: NP_001308781.1 UniProt: P23458

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

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: P23458
JAK1 ENST00000671929.2		c.3369+4T>G	splice_regionintron	Intron 25 of 25	Prot: ENSP00000500485.1 UniProt: P23458
JAK1 ENST00000671954.2		c.3369+4T>G	splice_regionintron	Intron 25 of 25	Prot: ENSP00000500841.1 UniProt: P23458

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

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score
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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence