6-3113257-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PP3_ModeratePP5BS1_Supporting

The NM_001354930.2(RIPK1):c.1934C>T(p.Thr645Met) variant causes a missense change. The variant allele was found at a frequency of 0.000117 in 1,614,098 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T645T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

RIPK1
NM_001354930.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 7.19

Publications

10 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
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:

LOC107986556 (HGNC:):

LOC107986556 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.863

PP5

Variant 6-3113257-C-T is Pathogenic according to our data. Variant chr6-3113257-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 598788.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000112 (17/152280) while in subpopulation NFE AF = 0.00022 (15/68028). AF 95% confidence interval is 0.000135. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK1	NM_001354930.2 link	c.1934C>T	p.Thr645Met	missense_variant	Exon 11 of 11	ENST00000259808.9	NP_001341859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPK1	ENST00000259808.9 link	c.1934C>T	p.Thr645Met	missense_variant	Exon 11 of 11	5	NM_001354930.2	ENSP00000259808.3		Q13546-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000558

AC:

AN:

251088

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000118

AC:

172

AN:

1461818

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000143

AC:

159

AN:

1111970

Other (OTH)

AF:

0.000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000112

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41550

American (AMR)

AF:

0.0000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000220

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Immunodeficiency 57

Pathogenic:3

Apr 19, 2019

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This c.1934C>T (p.T645M) variant has been previously reported in patients from two unrelated families with very early onset inflammatory bowel disease, diarrhea and recurrent infections [PMID 30591564] Functional studies showed that the T645M mutant proteins lead to impaired proinflammatory signaling, increased inflammasome activity and defective cell death response in intestinal epithelial cells [PMID 30591564] -

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 30591564). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.37). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with RIPK1 related disorder (ClinVar ID: VCV000598788 / PMID: 30591564). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Nov 09, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS3 supporting, PM2 supporting, PM3 strong, PP3 supporting -

Inborn error of immunity;C4749850:IL10-related early-onset inflammatory bowel disease

Pathogenic:1

Klein lab, Ludwig-Maximilians-University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

patients suffered from recurrent bacterial and/or viral infections and had episodes of diarrhea and/or colitis -

See cases

Pathogenic:1

Jul 28, 2023

Gene Friend Way, National Innovation Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This missense change has been observed in individual(s) with clinical features of RIPK1 deficiency (PMID: 30591564, 32181283). RIPK1 is an important regulator of inflammation and cell death. RIPK1-mediated necroptosis and neuroinflammation (PMID: 30467385), might contribute to the pathogenesis of Autism Spectrum disorder (ASD) (PMID: 31029798, 23147483). Many children with ASD experience diarhea and irritable bowel movement. In our study, an ASD patient carried this mutation. -

Autoinflammation with episodic fever and lymphadenopathy

Pathogenic:1

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 645 of the RIPK1 protein (p.Thr645Met). This variant is present in population databases (rs116040763, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of RIPK1 deficiency (PMID: 30591564, 32181283, 36466854, 36939041). ClinVar contains an entry for this variant (Variation ID: 598788). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RIPK1 function (PMID: 30591564). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

D;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

.;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

4.0

H;H

PhyloP100

7.2

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.80

MVP

0.98

MPC

0.83

ClinPred

1.0

GERP RS

5.9

Varity_R

0.62

gMVP

0.70

Mutation Taster

=8/92

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over