1-64955388-G-T

Variant names:

• chr1-64955388-G-T
• rs4244165
• NM_002227.4:c.-78+10945C>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002227.4(JAK1):​c.-78+10945C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 151,930 control chromosomes in the GnomAD database, including 25,435 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (25435 hom., cov: 32)
• Consequence: JAK1 NM_002227.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.879

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK1	NM_002227.4	c.-78+10945C>A		intron_variant	Intron 1 of 24	ENST00000342505.5	NP_002218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000342505.5	c.-78+10945C>A		intron_variant	Intron 1 of 24	5	NM_002227.4	ENSP00000343204.4

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80502 AN: 151812 Hom.: 25443 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.770

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.574

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.720

Gnomad OTH AF: 0.594

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.530 AC: 80489 AN: 151930 Hom.: 25435 Cov.: 32 AF XY: 0.527 AC XY: 39150 AN XY: 74230

Gnomad4 AFR AF: 0.181

Gnomad4 AMR AF: 0.569

Gnomad4 ASJ AF: 0.621

Gnomad4 EAS AF: 0.326

Gnomad4 SAS AF: 0.572

Gnomad4 FIN AF: 0.631

Gnomad4 NFE AF: 0.720

Gnomad4 OTH AF: 0.588

Alfa AF: 0.626 Hom.: 7410

Bravo AF: 0.510

Asia WGS AF: 0.421 AC: 1466 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.1
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs4244165; hg19: chr1-65421071; COSMIC: COSV61089203;