1-64850992-G-A

Variant names:

• chr1-64850992-G-A
• rs310216
• NM_002227.4:c.1649-82C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002227.4(JAK1):​c.1649-82C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 908,368 control chromosomes in the GnomAD database, including 38,936 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (10831 hom., cov: 32)
  • Exomes 𝑓: 0.26 (28105 hom.)
• Consequence: JAK1 NM_002227.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.197
• Publications: 11 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-64850992-G-A is Benign according to our data. Variant chr1-64850992-G-A is described in ClinVar as Benign. ClinVar VariationId is 2628196.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002227.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	NM_002227.4	MANE Select	c.1649-82C>T		intron	N/A	NP_002218.2
	JAK1	NM_001320923.2		c.1649-82C>T		intron	N/A	NP_001307852.1
	JAK1	NM_001321852.2		c.1649-82C>T		intron	N/A	NP_001308781.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK1	ENST00000342505.5	TSL:5 MANE Select	c.1649-82C>T		intron	N/A	ENSP00000343204.4
	JAK1	ENST00000671929.2		c.1649-82C>T		intron	N/A	ENSP00000500485.1
	JAK1	ENST00000671954.2		c.1649-82C>T		intron	N/A	ENSP00000500841.1

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52800 AN: 151932 Hom.: 10793 Cov.: 32

Gnomad AFR AF: 0.578

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.331

GnomAD4 exome AF: 0.264 AC: 199858 AN: 756318 Hom.: 28105 AF XY: 0.261 AC XY: 103646 AN XY: 396802

African (AFR) AF: 0.584 AC: 11701 AN: 20032

American (AMR) AF: 0.345 AC: 12718 AN: 36900

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 7498 AN: 21168

East Asian (EAS) AF: 0.293 AC: 10165 AN: 34676

South Asian (SAS) AF: 0.231 AC: 15720 AN: 68110

European-Finnish (FIN) AF: 0.276 AC: 13621 AN: 49434

Middle Eastern (MID) AF: 0.267 AC: 1170 AN: 4378

European-Non Finnish (NFE) AF: 0.241 AC: 116868 AN: 484640

Other (OTH) AF: 0.281 AC: 10397 AN: 36980

GnomAD4 genome AF: 0.348 AC: 52897 AN: 152050 Hom.: 10831 Cov.: 32 AF XY: 0.347 AC XY: 25759 AN XY: 74316

African (AFR) AF: 0.578 AC: 23977 AN: 41450

American (AMR) AF: 0.306 AC: 4671 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 1238 AN: 3466

East Asian (EAS) AF: 0.294 AC: 1516 AN: 5152

South Asian (SAS) AF: 0.228 AC: 1101 AN: 4826

European-Finnish (FIN) AF: 0.286 AC: 3023 AN: 10572

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16434 AN: 67984

Other (OTH) AF: 0.338 AC: 713 AN: 2112

Alfa AF: 0.287 Hom.: 8861

Bravo AF: 0.362

Asia WGS AF: 0.309 AC: 1074 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.0
DANN	Benign	0.66
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs310216; hg19: chr1-65316675;