rs752183065

Variant names:

• chr6-3113167-T-C
• rs752183065
• NM_001354930.2:c.1844T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PP5

The NM_001354930.2(RIPK1):​c.1844T>C​(p.Ile615Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: RIPK1 NM_001354930.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.29
• Publications: 8 publications found

Genes affected

RIPK1 (HGNC:10019): (receptor interacting serine/threonine kinase 1) This gene encodes a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases. The encoded protein plays a role in inflammation and cell death in response to tissue damage, pathogen recognition, and as part of developmental regulation. RIPK1/RIPK3 kinase-mediated necrosis is referred to as necroptosis. Genetic disruption of this gene in mice results in death shortly after birth. [provided by RefSeq, Aug 2017]

RIPK1 Gene-Disease associations (from GenCC):

• immunodeficiency 57

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autoinflammation with episodic fever and lymphadenopathy

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC107986556 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836
• PP5: Variant 6-3113167-T-C is Pathogenic according to our data. Variant chr6-3113167-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 598787.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354930.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK1	NM_001354930.2	MANE Select	c.1844T>C	p.Ile615Thr	missense	Exon 11 of 11	NP_001341859.1	Q13546-1
	RIPK1	NM_003804.6		c.1844T>C	p.Ile615Thr	missense	Exon 11 of 11	NP_003795.2	Q13546-1
	RIPK1	NM_001354931.2		c.1706T>C	p.Ile569Thr	missense	Exon 10 of 10	NP_001341860.1	Q13546-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK1	ENST00000259808.9	TSL:5 MANE Select	c.1844T>C	p.Ile615Thr	missense	Exon 11 of 11	ENSP00000259808.3	Q13546-1
	RIPK1	ENST00000380409.3	TSL:1	c.1706T>C	p.Ile569Thr	missense	Exon 10 of 10	ENSP00000369773.3	Q13546-2
	RIPK1	ENST00000967583.1		c.1907T>C	p.Ile636Thr	missense	Exon 12 of 12	ENSP00000637642.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251074 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461744 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727160

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111932

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn error of immunity;C4749850:IL10-related early-onset inflammatory bowel disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.059	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.71		Loss of stability (P = 9e-04)
MVP		0.86
MPC		0.91
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.70
gMVP		0.79
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs752183065; hg19: chr6-3113401;