rs3746891

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000332512.8(RIPK4):c.1996A>G(p.Met666Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.969 in 1,610,228 control chromosomes in the GnomAD database, including 755,817 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.98 ( 72936 hom., cov: 36)

Exomes 𝑓: 0.97 ( 682881 hom. )

Consequence

RIPK4
ENST00000332512.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.675

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.0242087E-7).

BP6

Variant 21-41741197-T-C is Benign according to our data. Variant chr21-41741197-T-C is described in ClinVar as [Benign]. Clinvar id is 261350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-41741197-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.987 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIPK4	NM_020639.3 linkuse as main transcript	c.1996A>G	p.Met666Val	missense_variant	8/8	ENST00000332512.8	NP_065690.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIPK4	ENST00000332512.8 linkuse as main transcript	c.1996A>G	p.Met666Val	missense_variant	8/8	1	NM_020639.3	ENSP00000332454	P1	P57078-2
	ENST00000423276.1 linkuse as main transcript	n.350T>C		non_coding_transcript_exon_variant	2/2	3
RIPK4	ENST00000352483.3 linkuse as main transcript	c.2140A>G	p.Met714Val	missense_variant	9/9	5		ENSP00000330161		P57078-1

Frequencies

GnomAD3 genomes

AF:

0.978

AC:

148901

AN:

152204

Hom.:

72879

Cov.:

show subpopulations

Gnomad AFR

AF:

0.995

Gnomad AMI

AF:

0.997

Gnomad AMR

AF:

0.991

Gnomad ASJ

AF:

0.982

Gnomad EAS

AF:

0.919

Gnomad SAS

AF:

0.887

Gnomad FIN

AF:

0.993

Gnomad MID

AF:

0.987

Gnomad NFE

AF:

0.974

Gnomad OTH

AF:

0.980

GnomAD3 exomes

AF:

0.967

AC:

237922

AN:

246154

Hom.:

115118

AF XY:

0.963

AC XY:

128400

AN XY:

133378

show subpopulations

Gnomad AFR exome

AF:

0.996

Gnomad AMR exome

AF:

0.994

Gnomad ASJ exome

AF:

0.983

Gnomad EAS exome

AF:

0.918

Gnomad SAS exome

AF:

0.896

Gnomad FIN exome

AF:

0.991

Gnomad NFE exome

AF:

0.974

Gnomad OTH exome

AF:

0.973

GnomAD4 exome

AF:

0.968

AC:

1410648

AN:

1457906

Hom.:

682881

Cov.:

AF XY:

0.966

AC XY:

699989

AN XY:

724970

show subpopulations

Gnomad4 AFR exome

AF:

0.997

Gnomad4 AMR exome

AF:

0.994

Gnomad4 ASJ exome

AF:

0.984

Gnomad4 EAS exome

AF:

0.909

Gnomad4 SAS exome

AF:

0.897

Gnomad4 FIN exome

AF:

0.990

Gnomad4 NFE exome

AF:

0.972

Gnomad4 OTH exome

AF:

0.965

GnomAD4 genome

AF:

0.978

AC:

149018

AN:

152322

Hom.:

72936

Cov.:

AF XY:

0.978

AC XY:

72805

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.995

Gnomad4 AMR

AF:

0.991

Gnomad4 ASJ

AF:

0.982

Gnomad4 EAS

AF:

0.919

Gnomad4 SAS

AF:

0.886

Gnomad4 FIN

AF:

0.993

Gnomad4 NFE

AF:

0.974

Gnomad4 OTH

AF:

0.979

Alfa

AF:

0.973

Hom.:

146692

Bravo

AF:

0.981

TwinsUK

AF:

0.973

AC:

3609

ALSPAC

AF:

0.976

AC:

3760

ESP6500AA

AF:

0.994

AC:

4380

ESP6500EA

AF:

0.973

AC:

8366

ExAC

AF:

0.965

AC:

116973

Asia WGS

AF:

0.918

AC:

3193

AN:

3478

EpiCase

AF:

0.972

EpiControl

AF:

0.973

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bartsocas-Papas syndrome 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.67

CADD

Benign

5.3

DANN

Benign

0.54

DEOGEN2

Benign

0.036

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.075

T;T

MetaRNN

Benign

6.0e-7

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.65

N;.

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.050

N;N

REVEL

Benign

0.036

Sift

Benign

0.71

T;T

Sift4G

Benign

0.76

T;T

Polyphen

0.0

.;B

Vest4

0.0060

MPC

0.43

ClinPred

0.000017

GERP RS

-0.094

Varity_R

0.044

gMVP

0.12

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over