chr21-41741197-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020639.3(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. 16/21 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
NM_020639.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.675

Publications

28 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=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 VariationId is 261350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK4	NM_020639.3 link	c.1996A>G	p.Met666Val	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.1996A>G	p.Met666Val	missense_variant	Exon 8 of 8	1	NM_020639.3	ENSP00000332454.3	P57078-2
RIPK4	ENST00000352483.3 link	c.2140A>G	p.Met714Val	missense_variant	Exon 9 of 9	5		ENSP00000330161.2	P57078-1
ENSG00000236883	ENST00000423276.1 link	n.350T>C		non_coding_transcript_exon_variant	Exon 2 of 2	3

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

GnomAD2 exomes

AF:

0.967

AC:

237922

AN:

246154

AF XY:

0.963

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 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

African (AFR)

AF:

0.997

AC:

33323

AN:

33424

American (AMR)

AF:

0.994

AC:

44269

AN:

44556

Ashkenazi Jewish (ASJ)

AF:

0.984

AC:

25575

AN:

25992

East Asian (EAS)

AF:

0.909

AC:

36039

AN:

39642

South Asian (SAS)

AF:

0.897

AC:

77128

AN:

85954

European-Finnish (FIN)

AF:

0.990

AC:

51253

AN:

51766

Middle Eastern (MID)

AF:

0.974

AC:

5616

AN:

5764

European-Non Finnish (NFE)

AF:

0.972

AC:

1079329

AN:

1110568

Other (OTH)

AF:

0.965

AC:

58116

AN:

60240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

3230

6460

9689

12919

16149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21642

43284

64926

86568

108210

<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:

0.978

AC:

149018

AN:

152322

Hom.:

72936

Cov.:

AF XY:

0.978

AC XY:

72805

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.995

AC:

41357

AN:

41584

American (AMR)

AF:

0.991

AC:

15177

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.982

AC:

3408

AN:

3470

East Asian (EAS)

AF:

0.919

AC:

4752

AN:

5170

South Asian (SAS)

AF:

0.886

AC:

4274

AN:

4822

European-Finnish (FIN)

AF:

0.993

AC:

10551

AN:

10626

Middle Eastern (MID)

AF:

0.986

AC:

290

AN:

294

European-Non Finnish (NFE)

AF:

0.974

AC:

66230

AN:

68020

Other (OTH)

AF:

0.979

AC:

2070

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

175

350

525

700

875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.973

Hom.:

200594

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

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. -

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.

PhyloP100

0.68

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

Mutation Taster

=100/0

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