Genetic Variant RIPK1:p.Phe28Leu (chr6-3076907-T-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001317061.3(RIPK1):c.-520T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RIPK1
NM_001317061.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.23

Publications

38 publications found

Variant links:

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

RIPK1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317061.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIPK1	NM_001354930.2	MANE Select	c.84T>G	p.Phe28Leu	missense	Exon 2 of 11	NP_001341859.1	Q13546-1
RIPK1	NM_001317061.3		c.-520T>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 13	NP_001303990.1
RIPK1	NM_001354932.2		c.-520T>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 12	NP_001341861.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIPK1	ENST00000259808.9	TSL:5 MANE Select	c.84T>G	p.Phe28Leu	missense	Exon 2 of 11	ENSP00000259808.3	Q13546-1
RIPK1	ENST00000380409.3	TSL:1	c.84T>G	p.Phe28Leu	missense	Exon 2 of 10	ENSP00000369773.3	Q13546-2
RIPK1	ENST00000967583.1		c.84T>G	p.Phe28Leu	missense	Exon 2 of 12	ENSP00000637642.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1460870

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726830

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111214

Other (OTH)

AF:

0.00

AC:

AN:

60360

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

124852

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.57

MutationAssessor

Pathogenic

3.6

PhyloP100

-1.2

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.032

Polyphen

1.0

Vest4

0.66

MutPred

0.89

Gain of catalytic residue at F28 (P = 0.0876)

MVP

0.77

MPC

0.85

ClinPred

0.99

GERP RS

-2.6

Varity_R

0.77

gMVP

0.73

Mutation Taster

=59/41

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over