21-41766883-C-T

Variant names:

• chr21-41766883-C-T
• rs6586238
• NM_020639.3:c.159G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_020639.3(RIPK4):​c.159G>A​(p.Ser53Ser) 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:3
• Conservation: PhyloP100: 0.0540
• Publications: 13 publications found

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: G2P, Orphanet
• ectodermal dysplasia syndrome

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics

ENSG00000289513 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 340036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020639.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK4	NM_020639.3	MANE Select	c.159G>A	p.Ser53Ser	synonymous	Exon 1 of 8	NP_065690.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK4	ENST00000332512.8	TSL:1 MANE Select	c.159G>A	p.Ser53Ser	synonymous	Exon 1 of 8	ENSP00000332454.3	P57078-2
	RIPK4	ENST00000352483.3	TSL:5	c.159G>A	p.Ser53Ser	synonymous	Exon 1 of 9	ENSP00000330161.2	P57078-1
	ENSG00000289513	ENST00000827190.1		n.304+1754C>T		intron	N/A

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

GnomAD2 exomes AF: 0.106 AC: 25347 AN: 239656 AF XY: 0.105

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 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

African (AFR) AF: 0.186 AC: 6138 AN: 33000

American (AMR) AF: 0.0632 AC: 2820 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.0650 AC: 1693 AN: 26038

East Asian (EAS) AF: 0.000203 AC: 8 AN: 39400

South Asian (SAS) AF: 0.0609 AC: 5248 AN: 86146

European-Finnish (FIN) AF: 0.123 AC: 6385 AN: 52016

Middle Eastern (MID) AF: 0.0813 AC: 467 AN: 5746

European-Non Finnish (NFE) AF: 0.152 AC: 168890 AN: 1110518

Other (OTH) AF: 0.125 AC: 7523 AN: 60216

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

African (AFR) AF: 0.183 AC: 7599 AN: 41472

American (AMR) AF: 0.0971 AC: 1485 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0611 AC: 212 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5164

South Asian (SAS) AF: 0.0498 AC: 240 AN: 4818

European-Finnish (FIN) AF: 0.112 AC: 1190 AN: 10600

Middle Eastern (MID) AF: 0.0445 AC: 13 AN: 292

European-Non Finnish (NFE) AF: 0.145 AC: 9820 AN: 67902

Other (OTH) AF: 0.115 AC: 243 AN: 2112

Alfa AF: 0.133 Hom.: 3464

Bravo AF: 0.138

Asia WGS AF: 0.0360 AC: 126 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Bartsocas-Papas syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	14
DANN	Benign	0.97
PhyloP100		0.054
PromoterAI		-0.11	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6586238; hg19: chr21-43187043; COSMIC: COSV108126163;