rs35537517

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020639.3(RIPK4):c.2101C>T(p.Pro701Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00841 in 1,612,138 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0059 ( 7 hom., cov: 34)

Exomes 𝑓: 0.0087 ( 74 hom. )

Consequence

RIPK4
NM_020639.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.89

Publications

6 publications found

Variant links:

Genes affected

RIPK4 (HGNC:496): (receptor interacting serine/threonine kinase 4) The protein encoded by this gene is a serine/threonine protein kinase that interacts with protein kinase C-delta. The encoded protein can also activate NFkappaB and is required for keratinocyte differentiation. This kinase undergoes autophosphorylation. [provided by RefSeq, Jul 2008]

RIPK4 Gene-Disease associations (from GenCC):

Bartsocas-Papas syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
ectodermal dysplasia syndrome
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics

RIPK4 links:

ENSG00000236883 (HGNC:):

ENSG00000236883 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005151719).

BP6

Variant 21-41741092-G-A is Benign according to our data. Variant chr21-41741092-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00587 (894/152290) while in subpopulation NFE AF = 0.00929 (632/68026). AF 95% confidence interval is 0.00869. There are 7 homozygotes in GnomAd4. There are 435 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK4	NM_020639.3 link	c.2101C>T	p.Pro701Ser	missense_variant	Exon 8 of 8	ENST00000332512.8	NP_065690.2	Q9H4D1Q96T11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RIPK4	ENST00000332512.8 link	c.2101C>T	p.Pro701Ser	missense_variant	Exon 8 of 8	1	NM_020639.3	ENSP00000332454.3	P57078-2
RIPK4	ENST00000352483.3 link	c.2245C>T	p.Pro749Ser	missense_variant	Exon 9 of 9	5		ENSP00000330161.2	P57078-1
ENSG00000236883	ENST00000423276.1 link	n.300-55G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.00586

AC:

892

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.00798

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00927

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00605

AC:

1495

AN:

247236

AF XY:

0.00603

show subpopulations

Gnomad AFR exome

AF:

0.00150

Gnomad AMR exome

AF:

0.00573

Gnomad ASJ exome

AF:

0.00479

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000428

Gnomad NFE exome

AF:

0.00964

Gnomad OTH exome

AF:

0.00806

GnomAD4 exome

AF:

0.00867

AC:

12658

AN:

1459848

Hom.:

Cov.:

AF XY:

0.00836

AC XY:

6069

AN XY:

726288

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

33466

American (AMR)

AF:

0.00633

AC:

283

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00463

AC:

121

AN:

26110

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.00380

AC:

328

AN:

86206

European-Finnish (FIN)

AF:

0.000445

AC:

AN:

51730

Middle Eastern (MID)

AF:

0.00607

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0102

AC:

11355

AN:

1111810

Other (OTH)

AF:

0.00770

AC:

465

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

893

1786

2680

3573

4466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

438

876

1314

1752

2190

<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:

0.00587

AC:

894

AN:

152290

Hom.:

Cov.:

AF XY:

0.00584

AC XY:

435

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00181

AC:

AN:

41544

American (AMR)

AF:

0.00797

AC:

122

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.00290

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00929

AC:

632

AN:

68026

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00674

Hom.:

Bravo

AF:

0.00671

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.0101

AC:

ExAC

AF:

0.00558

AC:

677

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00949

EpiControl

AF:

0.0102

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 23, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 06, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RIPK4: BP4, BS1, BS2 -

Bartsocas-Papas syndrome 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

RIPK4-related disorder

Benign:1

Jan 31, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.056

T;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.15

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

D;D

MetaRNN

Benign

0.0052

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.30

N;.

PhyloP100

3.9

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.42

N;N

REVEL

Benign

0.22

Sift

Benign

0.63

T;T

Sift4G

Benign

0.69

T;T

Polyphen

1.0

.;D

Vest4

0.17

MVP

0.67

MPC

1.3

ClinPred

0.037

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.080

gMVP

0.27

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over