21-41756639-T-G

Variant names:

• chr21-41756639-T-G
• rs13049286
• NM_020639.3:c.360A>C

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.360A>C​(p.Arg120Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 1,613,896 control chromosomes in the GnomAD database, including 15,935 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1590 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14345 hom.)
• Consequence: RIPK4 NM_020639.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.630
• Publications: 19 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=-0.83).
• BP6: Variant 21-41756639-T-G is Benign according to our data. Variant chr21-41756639-T-G is described in ClinVar as Benign. ClinVar VariationId is 340031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.177 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.360A>C	p.Arg120Arg	synonymous	Exon 2 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.360A>C	p.Arg120Arg	synonymous	Exon 2 of 8	ENSP00000332454.3	P57078-2
	RIPK4	ENST00000352483.3	TSL:5	c.360A>C	p.Arg120Arg	synonymous	Exon 2 of 9	ENSP00000330161.2	P57078-1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21191 AN: 152052 Hom.: 1593 Cov.: 33

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.0369

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.0840

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.129 AC: 32464 AN: 251304 AF XY: 0.135

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.0740

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.0329

Gnomad FIN exome AF: 0.0860

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.135 AC: 197880 AN: 1461726 Hom.: 14345 Cov.: 33 AF XY: 0.138 AC XY: 100476 AN XY: 727168

African (AFR) AF: 0.170 AC: 5706 AN: 33480

American (AMR) AF: 0.0786 AC: 3517 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 5472 AN: 26136

East Asian (EAS) AF: 0.0284 AC: 1129 AN: 39700

South Asian (SAS) AF: 0.194 AC: 16707 AN: 86258

European-Finnish (FIN) AF: 0.0861 AC: 4585 AN: 53270

Middle Eastern (MID) AF: 0.227 AC: 1307 AN: 5768

European-Non Finnish (NFE) AF: 0.136 AC: 150700 AN: 1111994

Other (OTH) AF: 0.145 AC: 8757 AN: 60396

GnomAD4 genome AF: 0.139 AC: 21200 AN: 152170 Hom.: 1590 Cov.: 33 AF XY: 0.136 AC XY: 10111 AN XY: 74392

African (AFR) AF: 0.167 AC: 6922 AN: 41518

American (AMR) AF: 0.124 AC: 1890 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 728 AN: 3462

East Asian (EAS) AF: 0.0364 AC: 188 AN: 5170

South Asian (SAS) AF: 0.187 AC: 903 AN: 4822

European-Finnish (FIN) AF: 0.0840 AC: 890 AN: 10596

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9177 AN: 67986

Other (OTH) AF: 0.154 AC: 325 AN: 2116

Alfa AF: 0.139 Hom.: 2472

Bravo AF: 0.142

Asia WGS AF: 0.118 AC: 412 AN: 3478

EpiCase AF: 0.147

EpiControl AF: 0.148

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.38
PhyloP100		-0.63
Mutation Taster		=99/1	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: rs13049286; hg19: chr21-43176799; COSMIC: COSV60185313;