rs55812846

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_020639.3(RIPK4):c.1884C>T(p.Ser628Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,608,500 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 8 hom., cov: 35)

Exomes 𝑓: 0.0054 ( 34 hom. )

Consequence

RIPK4
NM_020639.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -4.91

Publications

1 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 21-41741309-G-A is Benign according to our data. Variant chr21-41741309-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.91 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00474 (722/152298) while in subpopulation NFE AF = 0.00541 (368/68010). AF 95% confidence interval is 0.00496. There are 8 homozygotes in GnomAd4. There are 343 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK4	NM_020639.3 link	c.1884C>T	p.Ser628Ser	synonymous_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.1884C>T	p.Ser628Ser	synonymous_variant	Exon 8 of 8	1	NM_020639.3	ENSP00000332454.3	P57078-2
RIPK4	ENST00000352483.3 link	c.2028C>T	p.Ser676Ser	synonymous_variant	Exon 9 of 9	5		ENSP00000330161.2	P57078-1
ENSG00000236883	ENST00000423276.1 link	n.*1G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00474

AC:

722

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.0681

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0132

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00541

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00538

AC:

1310

AN:

243718

AF XY:

0.00546

show subpopulations

Gnomad AFR exome

AF:

0.00133

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.0105

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.0152

Gnomad NFE exome

AF:

0.00724

Gnomad OTH exome

AF:

0.00398

GnomAD4 exome

AF:

0.00536

AC:

7803

AN:

1456202

Hom.:

Cov.:

AF XY:

0.00526

AC XY:

3813

AN XY:

724708

show subpopulations

African (AFR)

AF:

0.000867

AC:

AN:

33464

American (AMR)

AF:

0.00168

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00989

AC:

258

AN:

26090

East Asian (EAS)

AF:

0.00123

AC:

AN:

39680

South Asian (SAS)

AF:

0.00113

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.0136

AC:

657

AN:

48302

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00568

AC:

6310

AN:

1111668

Other (OTH)

AF:

0.00444

AC:

268

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

562

1124

1687

2249

2811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

240

480

720

960

1200

<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:

0.00474

AC:

722

AN:

152298

Hom.:

Cov.:

AF XY:

0.00461

AC XY:

343

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

41568

American (AMR)

AF:

0.00248

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.00186

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0132

AC:

140

AN:

10626

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00541

AC:

368

AN:

68010

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

116

155

194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00555

Hom.:

Bravo

AF:

0.00420

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00567

EpiControl

AF:

0.00545

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Sep 28, 2016

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

Nov 19, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as 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

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.32

(source)

DANN

Benign

0.87

PhyloP100

-4.9

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