rs148192173

chr21-41741185-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.79

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]

(HGNC:):

ACMG classification

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
RIPK4	NM_020639.3	c.2008G>A	p.Gly670Ser	missense_variant	8/8	ENST00000332512.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPK4	ENST00000332512.8	c.2008G>A	p.Gly670Ser	missense_variant	8/8	1	NM_020639.3	P1
	ENST00000423276.1	n.338C>T		non_coding_transcript_exon_variant	2/2	3
RIPK4	ENST00000352483.3	c.2152G>A	p.Gly718Ser	missense_variant	9/9	5

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152238 Hom.: 1 Cov.: 34

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

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

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

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 05, 2017

- -

Bartsocas-Papas syndrome 1 Uncertain:1

Uncertain significance, 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, 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 submitter

clinical testing

GeneDx

Jul 09, 2020

In 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

Other links and lift over

dbSNP: rs148192173; hg19: chr21-43161345;