rs6586238

chr21-41766883-C-Tchr21-41766883-C-Achr21-41766883-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_020639.3(RIPK4):c.159G>A(p.Ser53=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,609,716 control chromosomes in the GnomAD database, including 16,468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S53S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1554 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14914 hom.)
• Consequence: RIPK4 NM_020639.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0540

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 21-41766883-C-T is Benign according to our data. Variant chr21-41766883-C-T is described in ClinVar as [Benign]. Clinvar id is 340036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-41766883-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIPK4	NM_020639.3	c.159G>A	p.Ser53=	synonymous_variant	1/8	ENST00000332512.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPK4	ENST00000332512.8	c.159G>A	p.Ser53=	synonymous_variant	1/8	1	NM_020639.3	P1
RIPK4	ENST00000352483.3	c.159G>A	p.Ser53=	synonymous_variant	1/9	5

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20854 AN: 151928 Hom.: 1551 Cov.: 33

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.0681

Gnomad AMR AF: 0.0973

Gnomad ASJ AF: 0.0611

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0502

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.106 AC: 25347 AN: 239656 Hom.: 1710 AF XY: 0.105 AC XY: 13792 AN XY: 131546

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.0579

Gnomad ASJ exome AF: 0.0645

Gnomad EAS exome AF: 0.000452

Gnomad SAS exome AF: 0.0601

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.137 AC: 199172 AN: 1457676 Hom.: 14914 Cov.: 33 AF XY: 0.133 AC XY: 96794 AN XY: 725122

Gnomad4 AFR exome AF: 0.186

Gnomad4 AMR exome AF: 0.0632

Gnomad4 ASJ exome AF: 0.0650

Gnomad4 EAS exome AF: 0.000203

Gnomad4 SAS exome AF: 0.0609

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.137 AC: 20866 AN: 152040 Hom.: 1554 Cov.: 33 AF XY: 0.132 AC XY: 9792 AN XY: 74342

Gnomad4 AFR AF: 0.183

Gnomad4 AMR AF: 0.0971

Gnomad4 ASJ AF: 0.0611

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0498

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.145

Gnomad4 OTH AF: 0.115

Alfa AF: 0.131 Hom.: 2887

Bravo AF: 0.138

Asia WGS AF: 0.0360 AC: 126 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bartsocas-Papas syndrome 1 Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 02, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
Cadd	Benign	14
Dann	Benign	0.97

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: rs6586238; hg19: chr21-43187043;