21-41766883-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_020639.3(RIPK4):c.159G>A(p.Ser53Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,609,716 control chromosomes in the GnomAD database, including 16,468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S53S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.14 ( 1554 hom., cov: 33)

Exomes 𝑓: 0.14 ( 14914 hom. )

Consequence

RIPK4
NM_020639.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0540

Publications

13 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:

ENSG00000289513 (HGNC:):

ENSG00000289513 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.25).

BP6

Variant 21-41766883-C-T is Benign according to our data. Variant chr21-41766883-C-T is described in ClinVar as Benign. ClinVar VariationId is 340036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK4	NM_020639.3 link	c.159G>A	p.Ser53Ser	synonymous_variant	Exon 1 of 8	ENST00000332512.8	NP_065690.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RIPK4	ENST00000332512.8 link	c.159G>A	p.Ser53Ser	synonymous_variant	Exon 1 of 8	1	NM_020639.3	ENSP00000332454.3
RIPK4	ENST00000352483.3 link	c.159G>A	p.Ser53Ser	synonymous_variant	Exon 1 of 9	5		ENSP00000330161.2
ENSG00000289513	ENST00000827190.1 link	n.304+1754C>T		intron_variant	Intron 1 of 1
ENSG00000289513	ENST00000827191.1 link	n.125+1754C>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.137

AC:

20854

AN:

151928

Hom.:

1551

Cov.:

show subpopulations

Gnomad AFR

AF:

0.183

Gnomad AMI

AF:

0.0681

Gnomad AMR

AF:

0.0973

Gnomad ASJ

AF:

0.0611

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0502

Gnomad FIN

AF:

0.112

Gnomad MID

AF:

0.0510

Gnomad NFE

AF:

0.145

Gnomad OTH

AF:

0.116

GnomAD2 exomes

AF:

0.106

AC:

25347

AN:

239656

AF XY:

0.105

show subpopulations

Gnomad AFR exome

AF:

0.188

Gnomad AMR exome

AF:

0.0579

Gnomad ASJ exome

AF:

0.0645

Gnomad EAS exome

AF:

0.000452

Gnomad FIN exome

AF:

0.122

Gnomad NFE exome

AF:

0.141

Gnomad OTH exome

AF:

0.108

GnomAD4 exome

AF:

0.137

AC:

199172

AN:

1457676

Hom.:

14914

Cov.:

AF XY:

0.133

AC XY:

96794

AN XY:

725122

show subpopulations

African (AFR)

AF:

0.186

AC:

6138

AN:

33000

American (AMR)

AF:

0.0632

AC:

2820

AN:

44596

Ashkenazi Jewish (ASJ)

AF:

0.0650

AC:

1693

AN:

26038

East Asian (EAS)

AF:

0.000203

AC:

AN:

39400

South Asian (SAS)

AF:

0.0609

AC:

5248

AN:

86146

European-Finnish (FIN)

AF:

0.123

AC:

6385

AN:

52016

Middle Eastern (MID)

AF:

0.0813

AC:

467

AN:

5746

European-Non Finnish (NFE)

AF:

0.152

AC:

168890

AN:

1110518

Other (OTH)

AF:

0.125

AC:

7523

AN:

60216

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

9785

19569

29354

39138

48923

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5958

11916

17874

23832

29790

<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:

0.137

AC:

20866

AN:

152040

Hom.:

1554

Cov.:

AF XY:

0.132

AC XY:

9792

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.183

AC:

7599

AN:

41472

American (AMR)

AF:

0.0971

AC:

1485

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0611

AC:

212

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5164

South Asian (SAS)

AF:

0.0498

AC:

240

AN:

4818

European-Finnish (FIN)

AF:

0.112

AC:

1190

AN:

10600

Middle Eastern (MID)

AF:

0.0445

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.145

AC:

9820

AN:

67902

Other (OTH)

AF:

0.115

AC:

243

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

901

1802

2704

3605

4506

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

224

448

672

896

1120

<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:

0.133

Hom.:

3464

Bravo

AF:

0.138

Asia WGS

AF:

0.0360

AC:

126

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 02, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bartsocas-Papas syndrome 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

0.054

PromoterAI

-0.11

Neutral

(source)

Mutation Taster

=98/2

polymorphism (auto)

(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