rs478665

Positions:

• chr1-65049850-A-G

Variant summary

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

The NM_001321852.2(JAK1):​c.-78+17754T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0619 in 152,210 control chromosomes in the GnomAD database, including 537 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 0.062 (537 hom., cov: 32)
• Consequence: JAK1 NM_001321852.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.769

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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAK1	NM_001321852.2	c.-78+17754T>C		intron_variant
JAK1	NM_001321853.2	c.-162+16778T>C		intron_variant
JAK1	NM_001321854.2	c.-78+16778T>C		intron_variant
JAK1	XM_047419676.1	c.-78+17754T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAK1	ENST00000671954.2	c.-180-5268T>C		intron_variant				A1
JAK1	ENST00000672099.1	c.-384+17754T>C		intron_variant
JAK1	ENST00000672434.2	c.-162+16778T>C		intron_variant				A1

Frequencies

GnomAD3 genomes AF: 0.0618 AC: 9393 AN: 152092 Hom.: 534 Cov.: 32

Gnomad AFR AF: 0.0582

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0882

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0401

Gnomad OTH AF: 0.0703

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

GnomAD4 genome AF: 0.0619 AC: 9416 AN: 152210 Hom.: 537 Cov.: 32 AF XY: 0.0636 AC XY: 4736 AN XY: 74424

Gnomad4 AFR AF: 0.0583

Gnomad4 AMR AF: 0.0884

Gnomad4 ASJ AF: 0.0836

Gnomad4 EAS AF: 0.322

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.0233

Gnomad4 NFE AF: 0.0401

Gnomad4 OTH AF: 0.0743

Alfa AF: 0.0504 Hom.: 337

Bravo AF: 0.0701

Asia WGS AF: 0.216 AC: 750 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.6
DANN	Benign	0.59

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs478665; hg19: chr1-65515533;