rs55812846

Variant names:

• chr21-41741309-G-A
• rs55812846
• NM_020639.3:c.1884C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020639.3(RIPK4):​c.1884C>T​(p.Ser628Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,608,500 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 35)
  • Exomes 𝑓: 0.0054 (34 hom.)
• Consequence: RIPK4 NM_020639.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.91

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]

ENSG00000236883 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 21-41741309-G-A is Benign according to our data. Variant chr21-41741309-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 191165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-41741309-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.91 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00474 (722/152298) while in subpopulation NFE AF= 0.00541 (368/68010). AF 95% confidence interval is 0.00496. There are 8 homozygotes in gnomad4. There are 343 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK4	NM_020639.3	c.1884C>T	p.Ser628Ser	synonymous_variant	Exon 8 of 8	ENST00000332512.8	NP_065690.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPK4	ENST00000332512.8	c.1884C>T	p.Ser628Ser	synonymous_variant	Exon 8 of 8	1	NM_020639.3	ENSP00000332454.3
RIPK4	ENST00000352483.3	c.2028C>T	p.Ser676Ser	synonymous_variant	Exon 9 of 9	5		ENSP00000330161.2
ENSG00000236883	ENST00000423276.1	n.*1G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 722 AN: 152180 Hom.: 8 Cov.: 35

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.0681

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00541

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00538 AC: 1310 AN: 243718 Hom.: 5 AF XY: 0.00546 AC XY: 724 AN XY: 132720

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.00724

Gnomad OTH exome AF: 0.00398

GnomAD4 exome AF: 0.00536 AC: 7803 AN: 1456202 Hom.: 34 Cov.: 92 AF XY: 0.00526 AC XY: 3813 AN XY: 724708

Gnomad4 AFR exome AF: 0.000867

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.00989

Gnomad4 EAS exome AF: 0.00123

Gnomad4 SAS exome AF: 0.00113

Gnomad4 FIN exome AF: 0.0136

Gnomad4 NFE exome AF: 0.00568

Gnomad4 OTH exome AF: 0.00444

GnomAD4 genome AF: 0.00474 AC: 722 AN: 152298 Hom.: 8 Cov.: 35 AF XY: 0.00461 AC XY: 343 AN XY: 74484

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0132

Gnomad4 NFE AF: 0.00541

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00649 Hom.: 2

Bravo AF: 0.00420

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00567

EpiControl AF: 0.00545

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Sep 28, 2016

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Bartsocas-Papas syndrome 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

RIPK4-related disorder Benign:1

Nov 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.32
DANN	Benign	0.87

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: rs55812846; hg19: chr21-43161469; COSMIC: COSV60188551; COSMIC: COSV60188551;