Genetic Variant NM_020639.3:c.242T>A (chr21-41756757-A-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_020639.3(RIPK4):c.242T>A(p.Ile81Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RIPK4
NM_020639.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.08

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.914

PP5

Variant 21-41756757-A-T is Pathogenic according to our data. Variant chr21-41756757-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30512.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK4	NM_020639.3 link	c.242T>A	p.Ile81Asn	missense_variant	Exon 2 of 8	ENST00000332512.8	NP_065690.2	Q9H4D1Q96T11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPK4	ENST00000332512.8 link	c.242T>A	p.Ile81Asn	missense_variant	Exon 2 of 8	1	NM_020639.3	ENSP00000332454.3		P57078-2
RIPK4	ENST00000352483.3 link	c.242T>A	p.Ile81Asn	missense_variant	Exon 2 of 9	5		ENSP00000330161.2		P57078-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251414

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111966

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Bartsocas-Papas syndrome 1

Pathogenic:1

Jan 13, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

T;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Pathogenic

2.9

M;M

PhyloP100

9.1

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.95

.;P

Vest4

0.84

MutPred

0.75

Gain of catalytic residue at I81 (P = 0.0034);Gain of catalytic residue at I81 (P = 0.0034);

MVP

0.95

MPC

1.7

ClinPred

0.99

GERP RS

5.0

Varity_R

0.93

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over