21-41741092-G-A

Position:

chr21-41741092-G-A

Variant summary

Our verdict is Benign. Variant got -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. 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

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=0.005151719).

BP6

Variant 21-41741092-G-A is Benign according to our data. Variant chr21-41741092-G-A is described in ClinVar as [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIPK4	NM_020639.3 linkuse as main transcript	c.2101C>T	p.Pro701Ser	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.2101C>T	p.Pro701Ser	missense_variant	8/8	1	NM_020639.3	ENSP00000332454	P1	P57078-2
	ENST00000423276.1 linkuse as main transcript	n.300-55G>A		intron_variant, non_coding_transcript_variant		3
RIPK4	ENST00000352483.3 linkuse as main transcript	c.2245C>T	p.Pro749Ser	missense_variant	9/9	5		ENSP00000330161		P57078-1

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

GnomAD3 exomes

AF:

0.00605

AC:

1495

AN:

247236

Hom.:

AF XY:

0.00603

AC XY:

809

AN XY:

134096

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 SAS exome

AF:

0.00327

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

Gnomad4 AFR exome

AF:

0.00140

Gnomad4 AMR exome

AF:

0.00633

Gnomad4 ASJ exome

AF:

0.00463

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00380

Gnomad4 FIN exome

AF:

0.000445

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.00770

GnomAD4 genome

AF:

0.00587

AC:

894

AN:

152290

Hom.:

Cov.:

AF XY:

0.00584

AC XY:

435

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00181

Gnomad4 AMR

AF:

0.00797

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00929

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.00661

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RIPK4: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 23, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Bartsocas-Papas syndrome 1

Benign:1

Likely 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 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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2020

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

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;.

MutationTaster

Benign

0.89

D;D;D;D

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

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