chr6-3076950-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BS1_Supporting

The NM_001354930.2(RIPK1):c.127A>T(p.Ile43Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000912 in 1,611,694 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000084 ( 1 hom. )

Consequence

RIPK1
NM_001354930.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.42

Publications

4 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.38593936).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000158 (24/151704) while in subpopulation AMR AF = 0.000722 (11/15228). AF 95% confidence interval is 0.000404. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.127A>T	p.Ile43Phe	missense	Exon 2 of 11	NP_001341859.1	Q13546-1
RIPK1	NM_003804.6		c.127A>T	p.Ile43Phe	missense	Exon 2 of 11	NP_003795.2	Q13546-1
RIPK1	NM_001354931.2		c.127A>T	p.Ile43Phe	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.127A>T	p.Ile43Phe	missense	Exon 2 of 11	ENSP00000259808.3	Q13546-1
RIPK1	ENST00000380409.3	TSL:1	c.127A>T	p.Ile43Phe	missense	Exon 2 of 10	ENSP00000369773.3	Q13546-2
RIPK1	ENST00000967583.1		c.127A>T	p.Ile43Phe	missense	Exon 2 of 12	ENSP00000637642.1

Frequencies

GnomAD3 genomes

AF:

0.000152

AC:

AN:

151588

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000172

AC:

AN:

250556

AF XY:

0.000192

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000468

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000842

AC:

123

AN:

1459990

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

726274

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33444

American (AMR)

AF:

0.000538

AC:

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.000209

AC:

AN:

85938

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

5390

European-Non Finnish (NFE)

AF:

0.0000405

AC:

AN:

1111164

Other (OTH)

AF:

0.000265

AC:

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.000158

AC:

AN:

151704

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74144

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41306

American (AMR)

AF:

0.000722

AC:

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.000209

AC:

AN:

4788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10516

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67932

Other (OTH)

AF:

0.00

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.536

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:

0.000148

Hom.:

Bravo

AF:

0.000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000140

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

Eigen

Benign

0.12

Eigen_PC

Benign

0.030

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.78

M_CAP

Benign

0.055

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.66

PhyloP100

1.4

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.30

Sift

Uncertain

0.0040

Sift4G

Benign

0.061

Polyphen

1.0

Vest4

0.70

MVP

0.80

MPC

1.0

ClinPred

0.12

GERP RS

1.9

Varity_R

0.75

gMVP

0.91

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over