6-3076905-T-C

Position:

chr6-3076905-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_001354930.2(RIPK1):c.82T>C(p.Phe28Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000483 in 1,611,834 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00044 ( 1 hom., cov: 27)

Exomes 𝑓: 0.00049 ( 2 hom. )

Consequence

RIPK1
NM_001354930.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.47

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000442 (67/151432) while in subpopulation AMR AF= 0.00158 (24/15198). AF 95% confidence interval is 0.00109. There are 1 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIPK1	NM_001354930.2 linkuse as main transcript	c.82T>C	p.Phe28Leu	missense_variant	2/11	ENST00000259808.9	NP_001341859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIPK1	ENST00000259808.9 linkuse as main transcript	c.82T>C	p.Phe28Leu	missense_variant	2/11	5	NM_001354930.2	ENSP00000259808	P1	Q13546-1

Frequencies

GnomAD3 genomes

AF:

0.000442

AC:

AN:

151432

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00158

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000836

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000486

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000354

AC:

AN:

251342

Hom.:

AF XY:

0.000353

AC XY:

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000492

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000488

AC:

712

AN:

1460402

Hom.:

Cov.:

AF XY:

0.000442

AC XY:

321

AN XY:

726620

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000452

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000573

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000442

AC:

AN:

151432

Hom.:

Cov.:

AF XY:

0.000541

AC XY:

AN XY:

73928

show subpopulations

Gnomad4 AFR

AF:

0.000146

Gnomad4 AMR

AF:

0.00158

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000836

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000486

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000455

Hom.:

Bravo

AF:

0.000370

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000379

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency 57;C5394286:Autoinflammation with episodic fever and lymphadenopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 12, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 28 of the RIPK1 protein (p.Phe28Leu). This variant is present in population databases (rs146652253, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with RIPK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1445799). 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. 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

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.62

D;D

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

.;D

M_CAP

Uncertain

0.087

MetaRNN

Uncertain

0.68

D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Pathogenic

3.6

H;H

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-5.4

D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.032

D;D

Polyphen

1.0

D;D

Vest4

0.66

MutPred

0.89

Gain of catalytic residue at F28 (P = 0.0876);Gain of catalytic residue at F28 (P = 0.0876);

MVP

0.90

MPC

0.85

ClinPred

0.66

GERP RS

5.6

Varity_R

0.69

gMVP

0.73

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over