rs148192173

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_020639.3(RIPK4):​c.2008G>A​(p.Gly670Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00015 in 1,611,728 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00076 ( 1 hom., cov: 34)
Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

RIPK4
NM_020639.3 missense

Scores

4
10
5

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.79
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.026396245).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000761 (116/152356) while in subpopulation AFR AF= 0.00236 (98/41588). AF 95% confidence interval is 0.00198. There are 1 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RIPK4NM_020639.3 linkuse as main transcriptc.2008G>A p.Gly670Ser missense_variant 8/8 ENST00000332512.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RIPK4ENST00000332512.8 linkuse as main transcriptc.2008G>A p.Gly670Ser missense_variant 8/81 NM_020639.3 P1P57078-2
ENST00000423276.1 linkuse as main transcriptn.338C>T non_coding_transcript_exon_variant 2/23
RIPK4ENST00000352483.3 linkuse as main transcriptc.2152G>A p.Gly718Ser missense_variant 9/95 P57078-1

Frequencies

GnomAD3 genomes
AF:
0.000769
AC:
117
AN:
152238
Hom.:
1
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00236
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000850
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000223
AC:
55
AN:
246624
Hom.:
0
AF XY:
0.000172
AC XY:
23
AN XY:
133644
show subpopulations
Gnomad AFR exome
AF:
0.00267
Gnomad AMR exome
AF:
0.000203
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000988
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000907
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000857
AC:
125
AN:
1459372
Hom.:
0
Cov.:
84
AF XY:
0.0000703
AC XY:
51
AN XY:
725884
show subpopulations
Gnomad4 AFR exome
AF:
0.00224
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.000761
AC:
116
AN:
152356
Hom.:
1
Cov.:
34
AF XY:
0.000671
AC XY:
50
AN XY:
74498
show subpopulations
Gnomad4 AFR
AF:
0.00236
Gnomad4 AMR
AF:
0.000849
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000267
Hom.:
0
Bravo
AF:
0.000854
ESP6500AA
AF:
0.00182
AC:
8
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000247
AC:
30
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJan 05, 2017- -
Bartsocas-Papas syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 09, 2020In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.022
T
BayesDel_noAF
Pathogenic
0.19
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
T;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Pathogenic
0.38
D
MetaRNN
Benign
0.026
T;T
MetaSVM
Uncertain
0.45
D
MutationAssessor
Uncertain
2.7
M;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-3.6
D;D
REVEL
Pathogenic
0.72
Sift
Uncertain
0.0060
D;D
Sift4G
Uncertain
0.014
D;D
Polyphen
1.0
.;D
Vest4
0.57
MVP
0.91
MPC
1.3
ClinPred
0.099
T
GERP RS
4.5
Varity_R
0.42
gMVP
0.73

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.

Other links and lift over

dbSNP: rs148192173; hg19: chr21-43161345; API