6-3076908-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_StrongBS1

The NM_001354930.2(RIPK1):c.85G>A(p.Gly29Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000869 in 1,611,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

RIPK1
NM_001354930.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.55

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00000753 (11/1460354) while in subpopulation EAS AF = 0.000126 (5/39688). AF 95% confidence interval is 0.0000491. There are 0 homozygotes in GnomAdExome4. There are 6 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIPK1	NM_001354930.2	MANE Select	c.85G>A	p.Gly29Arg	missense	Exon 2 of 11	NP_001341859.1	Q13546-1
RIPK1	NM_003804.6		c.85G>A	p.Gly29Arg	missense	Exon 2 of 11	NP_003795.2	Q13546-1
RIPK1	NM_001354931.2		c.85G>A	p.Gly29Arg	missense	Exon 2 of 10	NP_001341860.1	Q13546-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIPK1	ENST00000259808.9	TSL:5 MANE Select	c.85G>A	p.Gly29Arg	missense	Exon 2 of 11	ENSP00000259808.3	Q13546-1
RIPK1	ENST00000380409.3	TSL:1	c.85G>A	p.Gly29Arg	missense	Exon 2 of 10	ENSP00000369773.3	Q13546-2
RIPK1	ENST00000967583.1		c.85G>A	p.Gly29Arg	missense	Exon 2 of 12	ENSP00000637642.1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151598

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251250

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460354

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726566

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.0000447

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.000126

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1110848

Other (OTH)

AF:

0.00

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.0000198

AC:

AN:

151598

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74038

show subpopulations

African (AFR)

AF:

0.0000486

AC:

AN:

41184

American (AMR)

AF:

0.0000658

AC:

AN:

15208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67934

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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:

0.00

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.61

MutationAssessor

Pathogenic

4.0

PhyloP100

5.6

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-7.3

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.89

MutPred

0.97

Gain of MoRF binding (P = 0.0201)

MVP

0.96

MPC

0.89

ClinPred

1.0

GERP RS

5.6

Varity_R

0.93

gMVP

0.92

Mutation Taster

=13/87

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over