Variant rs310229 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002227.4(JAK1):c.1459-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 1,606,088 control chromosomes in the GnomAD database, including 88,904 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 13244 hom., cov: 32)

Exomes 𝑓: 0.32 ( 75660 hom. )

Consequence

JAK1
NM_002227.4 splice_region, intron

Scores

Splicing: ADA: 0.00003188

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.269

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 links:

JAK1 (HGNC:):

JAK1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 1-64855705-G-A is Benign according to our data. Variant chr1-64855705-G-A is described in ClinVar as [Benign]. Clinvar id is 1169785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAK1	NM_002227.4 linkuse as main transcript	c.1459-7C>T		splice_region_variant, intron_variant		ENST00000342505.5	NP_002218.2	P23458

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5 linkuse as main transcript	c.1459-7C>T		splice_region_variant, intron_variant		5	NM_002227.4	ENSP00000343204.4		P23458

Frequencies

GnomAD3 genomes

AF:

0.399

AC:

60592

AN:

151784

Hom.:

13198

Cov.:

show subpopulations

Gnomad AFR

AF:

0.584

Gnomad AMI

AF:

0.232

Gnomad AMR

AF:

0.446

Gnomad ASJ

AF:

0.392

Gnomad EAS

AF:

0.309

Gnomad SAS

AF:

0.291

Gnomad FIN

AF:

0.328

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.306

Gnomad OTH

AF:

0.377

GnomAD3 exomes

AF:

0.359

AC:

87990

AN:

245004

Hom.:

16993

AF XY:

0.347

AC XY:

46218

AN XY:

133046

show subpopulations

Gnomad AFR exome

AF:

0.586

Gnomad AMR exome

AF:

0.520

Gnomad ASJ exome

AF:

0.391

Gnomad EAS exome

AF:

0.330

Gnomad SAS exome

AF:

0.301

Gnomad FIN exome

AF:

0.329

Gnomad NFE exome

AF:

0.303

Gnomad OTH exome

AF:

0.345

GnomAD4 exome

AF:

0.316

AC:

459018

AN:

1454186

Hom.:

75660

Cov.:

AF XY:

0.314

AC XY:

227173

AN XY:

722518

show subpopulations

Gnomad4 AFR exome

AF:

0.595

Gnomad4 AMR exome

AF:

0.510

Gnomad4 ASJ exome

AF:

0.389

Gnomad4 EAS exome

AF:

0.304

Gnomad4 SAS exome

AF:

0.297

Gnomad4 FIN exome

AF:

0.321

Gnomad4 NFE exome

AF:

0.299

Gnomad4 OTH exome

AF:

0.325

GnomAD4 genome

AF:

0.400

AC:

60699

AN:

151902

Hom.:

13244

Cov.:

AF XY:

0.399

AC XY:

29660

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.585

Gnomad4 AMR

AF:

0.447

Gnomad4 ASJ

AF:

0.392

Gnomad4 EAS

AF:

0.308

Gnomad4 SAS

AF:

0.292

Gnomad4 FIN

AF:

0.328

Gnomad4 NFE

AF:

0.306

Gnomad4 OTH

AF:

0.383

Alfa

AF:

0.359

Hom.:

4562

Bravo

AF:

0.418

Asia WGS

AF:

0.339

AC:

1179

AN:

3478

EpiCase

AF:

0.312

EpiControl

AF:

0.303

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 68% of patients studied by a panel of primary immunodeficiencies. Number of patients: 65. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

3.4

DANN

Benign

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000032

dbscSNV1_RF

Benign

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over