rs2838113

Variant names:

• chr21-41741645-G-A
• rs2838113
• NM_020639.3:c.1548C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020639.3(RIPK4):​c.1548C>T​(p.Asp516Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 1,613,212 control chromosomes in the GnomAD database, including 305,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23812 hom., cov: 34)
  • Exomes 𝑓: 0.62 (281362 hom.)
• Consequence: RIPK4 NM_020639.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.397
• Publications: 17 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 21-41741645-G-A is Benign according to our data. Variant chr21-41741645-G-A is described in ClinVar as Benign. ClinVar VariationId is 261349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.397 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.624 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.1548C>T	p.Asp516Asp	synonymous	Exon 8 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.1548C>T	p.Asp516Asp	synonymous	Exon 8 of 8	ENSP00000332454.3	P57078-2
	RIPK4	ENST00000352483.3	TSL:5	c.1692C>T	p.Asp564Asp	synonymous	Exon 9 of 9	ENSP00000330161.2	P57078-1

Frequencies

GnomAD3 genomes AF: 0.540 AC: 82148 AN: 152018 Hom.: 23819 Cov.: 34

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.581

GnomAD2 exomes AF: 0.608 AC: 152476 AN: 250904 AF XY: 0.617

Gnomad AFR exome AF: 0.298

Gnomad AMR exome AF: 0.611

Gnomad ASJ exome AF: 0.648

Gnomad EAS exome AF: 0.618

Gnomad FIN exome AF: 0.623

Gnomad NFE exome AF: 0.633

Gnomad OTH exome AF: 0.635

GnomAD4 exome AF: 0.618 AC: 903029 AN: 1461076 Hom.: 281362 Cov.: 79 AF XY: 0.620 AC XY: 450825 AN XY: 726904

African (AFR) AF: 0.296 AC: 9919 AN: 33480

American (AMR) AF: 0.612 AC: 27390 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 16946 AN: 26134

East Asian (EAS) AF: 0.632 AC: 25107 AN: 39700

South Asian (SAS) AF: 0.640 AC: 55246 AN: 86258

European-Finnish (FIN) AF: 0.615 AC: 32420 AN: 52688

Middle Eastern (MID) AF: 0.640 AC: 3693 AN: 5768

European-Non Finnish (NFE) AF: 0.626 AC: 695828 AN: 1111946

Other (OTH) AF: 0.604 AC: 36480 AN: 60380

GnomAD4 genome AF: 0.540 AC: 82156 AN: 152136 Hom.: 23812 Cov.: 34 AF XY: 0.543 AC XY: 40419 AN XY: 74372

African (AFR) AF: 0.306 AC: 12710 AN: 41504

American (AMR) AF: 0.622 AC: 9513 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2300 AN: 3472

East Asian (EAS) AF: 0.629 AC: 3245 AN: 5160

South Asian (SAS) AF: 0.636 AC: 3071 AN: 4832

European-Finnish (FIN) AF: 0.620 AC: 6561 AN: 10586

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.629 AC: 42713 AN: 67958

Other (OTH) AF: 0.579 AC: 1226 AN: 2116

Alfa AF: 0.603 Hom.: 44813

Bravo AF: 0.533

Asia WGS AF: 0.588 AC: 2045 AN: 3478

EpiCase AF: 0.638

EpiControl AF: 0.638

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.7
DANN	Benign	0.86
PhyloP100		0.40
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: rs2838113; hg19: chr21-43161805; COSMIC: COSV60185708; COSMIC: COSV60185708;