chr1-64833108-A-T

Variant names:

• chr1-64833108-A-T
• rs2780889
• NM_001366165.2:c.*2123A>T

Variant summary

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

The NM_001366165.2(RAVER2):​c.*2123A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 178,872 control chromosomes in the GnomAD database, including 25,746 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 0.51 (23084 hom., cov: 32)
  • Exomes 𝑓: 0.41 (2662 hom.)
• Consequence: RAVER2 NM_001366165.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.122
• Publications: 9 publications found

Genes affected

RAVER2 (HGNC:25577): (ribonucleoprotein, PTB binding 2) Enables RNA binding activity. Predicted to be involved in regulation of alternative mRNA splicing, via spliceosome. Predicted to be located in cytoplasm. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366165.2. 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
	RAVER2	NM_001366165.2	MANE Select	c.*2123A>T		3_prime_UTR	Exon 12 of 12	NP_001353094.1
	RAVER2	NM_018211.4		c.*2123A>T		3_prime_UTR	Exon 12 of 12	NP_060681.2
	JAK1	NM_002227.4	MANE Select	c.*1454T>A		downstream_gene	N/A	NP_002218.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAVER2	ENST00000294428.8	TSL:5 MANE Select	c.*2123A>T		3_prime_UTR	Exon 12 of 12	ENSP00000294428.3
	RAVER2	ENST00000371072.8	TSL:1	c.*2123A>T		3_prime_UTR	Exon 12 of 12	ENSP00000360112.4
	JAK1	ENST00000342505.5	TSL:5 MANE Select	c.*1454T>A		downstream_gene	N/A	ENSP00000343204.4

Frequencies

GnomAD3 genomes AF: 0.511 AC: 76940 AN: 150620 Hom.: 23029 Cov.: 32

Gnomad AFR AF: 0.841

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.417

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.470

GnomAD4 exome AF: 0.411 AC: 11568 AN: 28140 Hom.: 2662 Cov.: 0 AF XY: 0.405 AC XY: 5222 AN XY: 12898

African (AFR) AF: 0.837 AC: 787 AN: 940

American (AMR) AF: 0.412 AC: 243 AN: 590

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 792 AN: 1770

East Asian (EAS) AF: 0.572 AC: 3227 AN: 5640

South Asian (SAS) AF: 0.373 AC: 88 AN: 236

European-Finnish (FIN) AF: 0.389 AC: 84 AN: 216

Middle Eastern (MID) AF: 0.375 AC: 69 AN: 184

European-Non Finnish (NFE) AF: 0.329 AC: 5367 AN: 16310

Other (OTH) AF: 0.404 AC: 911 AN: 2254

GnomAD4 genome AF: 0.511 AC: 77058 AN: 150732 Hom.: 23084 Cov.: 32 AF XY: 0.510 AC XY: 37544 AN XY: 73628

African (AFR) AF: 0.841 AC: 34859 AN: 41462

American (AMR) AF: 0.417 AC: 6186 AN: 14826

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1631 AN: 3458

East Asian (EAS) AF: 0.617 AC: 3168 AN: 5134

South Asian (SAS) AF: 0.357 AC: 1700 AN: 4766

European-Finnish (FIN) AF: 0.406 AC: 4259 AN: 10482

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 23831 AN: 67312

Other (OTH) AF: 0.474 AC: 996 AN: 2100

Alfa AF: 0.464 Hom.: 2326

Bravo AF: 0.524

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.83
PhyloP100		0.12
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: rs2780889; hg19: chr1-65298791;