rs705509

Variant names:

• chr1-65066068-A-G
• rs705509
• NM_001321852.2:c.-78+1536T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-65066068-A-G
• chr1-65066068-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001321852.2(JAK1):​c.-78+1536T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 151,990 control chromosomes in the GnomAD database, including 14,188 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 0.37 (14188 hom., cov: 31)
• Consequence: JAK1 NM_001321852.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.110
• Publications: 5 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: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAK1	NM_001321852.2	c.-78+1536T>C		intron_variant	Intron 1 of 24		NP_001308781.1
JAK1	NM_001321853.2	c.-162+560T>C		intron_variant	Intron 2 of 26		NP_001308782.1
JAK1	NM_001321854.2	c.-78+560T>C		intron_variant	Intron 2 of 25		NP_001308783.1
JAK1	XM_047419676.1	c.-78+1536T>C		intron_variant	Intron 1 of 24		XP_047275632.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAK1	ENST00000671954.2	c.-181+1536T>C		intron_variant	Intron 1 of 25			ENSP00000500841.1
JAK1	ENST00000672434.2	c.-162+560T>C		intron_variant	Intron 2 of 26			ENSP00000499900.1
JAK1	ENST00000672751.2	c.-78+1536T>C		intron_variant	Intron 1 of 24			ENSP00000500745.2

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56626 AN: 151872 Hom.: 14136 Cov.: 31

Gnomad AFR AF: 0.703

Gnomad AMI AF: 0.223

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.558

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.197

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.351

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

GnomAD4 genome AF: 0.373 AC: 56738 AN: 151990 Hom.: 14188 Cov.: 31 AF XY: 0.374 AC XY: 27749 AN XY: 74264

African (AFR) AF: 0.703 AC: 29145 AN: 41440

American (AMR) AF: 0.263 AC: 4014 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 921 AN: 3466

East Asian (EAS) AF: 0.557 AC: 2839 AN: 5098

South Asian (SAS) AF: 0.337 AC: 1624 AN: 4824

European-Finnish (FIN) AF: 0.282 AC: 2982 AN: 10568

Middle Eastern (MID) AF: 0.202 AC: 59 AN: 292

European-Non Finnish (NFE) AF: 0.209 AC: 14193 AN: 68000

Other (OTH) AF: 0.359 AC: 758 AN: 2114

Alfa AF: 0.244 Hom.: 7961

Bravo AF: 0.387

Asia WGS AF: 0.472 AC: 1641 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.7
DANN	Benign	0.68
PhyloP100		0.11

Splicing

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

Other links and lift over

dbSNP: rs705509; hg19: chr1-65531751;